array:24 [
  "pii" => "S157921291930045X"
  "issn" => "15792129"
  "doi" => "10.1016/j.arbr.2018.07.017"
  "estado" => "S300"
  "fechaPublicacion" => "2019-03-01"
  "aid" => "1976"
  "copyright" => "SEPAR"
  "copyrightAnyo" => "2018"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "fla"
  "cita" => "Arch Bronconeumol. 2019;55:128-33"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 504
    "formatos" => array:3 [
      "EPUB" => 47
      "HTML" => 337
      "PDF" => 120
    ]
  ]
  "Traduccion" => array:1 [
    "en" => array:19 [
      "pii" => "S0300289618303144"
      "issn" => "03002896"
      "doi" => "10.1016/j.arbres.2018.07.021"
      "estado" => "S300"
      "fechaPublicacion" => "2019-03-01"
      "aid" => "1976"
      "copyright" => "SEPAR"
      "documento" => "article"
      "crossmark" => 1
      "subdocumento" => "fla"
      "cita" => "Arch Bronconeumol. 2019;55:128-33"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:2 [
        "total" => 867
        "formatos" => array:3 [
          "EPUB" => 65
          "HTML" => 622
          "PDF" => 180
        ]
      ]
      "en" => array:14 [
        "idiomaDefecto" => true
        "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
        "titulo" => "Association of <span class="elsevierStyleItalic">HTR2A</span>-1438G&#47;A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease"
        "tienePdf" => "en"
        "tieneTextoCompleto" => "en"
        "tieneResumen" => array:3 [
          0 => "en"
          1 => "en"
          2 => "es"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "128"
            "paginaFinal" => "133"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "es" => array:1 [
            "titulo" => "Asociaci&#243;n del polimorfismo gen&#233;tico <span class="elsevierStyleItalic">HTR2A</span>-1438G&#47;A con el tabaco y la enfermedad pulmonar obstructiva cr&#243;nica"
          ]
        ]
        "contieneResumen" => array:2 [
          "en" => true
          "es" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "en" => true
        ]
        "contienePdf" => array:1 [
          "en" => true
        ]
        "resumenGrafico" => array:2 [
          "original" => 1
          "multimedia" => array:5 [
            "identificador" => "fig0005"
            "tipo" => "MULTIMEDIAFIGURA"
            "mostrarFloat" => false
            "mostrarDisplay" => true
            "figura" => array:1 [
              0 => array:4 [
                "imagen" => "fx1.jpeg"
                "Alto" => 354
                "Ancho" => 1333
                "Tamanyo" => 79499
              ]
            ]
          ]
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "Zoraida Verde, Catalina Santiago, Luis M&#46; Chicharro, Fernando Bandr&#233;s, F&#233;lix G&#243;mez-Gallego, Jose Miguel Rodr&#237;guez Gonz&#225;lez-Moro, Pilar de Lucas"
            "autores" => array:7 [
              0 => array:2 [
                "nombre" => "Zoraida"
                "apellidos" => "Verde"
              ]
              1 => array:2 [
                "nombre" => "Catalina"
                "apellidos" => "Santiago"
              ]
              2 => array:2 [
                "nombre" => "Luis M&#46;"
                "apellidos" => "Chicharro"
              ]
              3 => array:2 [
                "nombre" => "Fernando"
                "apellidos" => "Bandr&#233;s"
              ]
              4 => array:2 [
                "nombre" => "F&#233;lix"
                "apellidos" => "G&#243;mez-Gallego"
              ]
              5 => array:2 [
                "nombre" => "Jose Miguel"
                "apellidos" => "Rodr&#237;guez Gonz&#225;lez-Moro"
              ]
              6 => array:2 [
                "nombre" => "Pilar"
                "apellidos" => "de Lucas"
              ]
            ]
          ]
        ]
        "resumen" => array:1 [
          0 => array:3 [
            "titulo" => "Graphical abstract"
            "clase" => "graphical"
            "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="fig0005"></elsevierMultimedia></p></span>"
          ]
        ]
      ]
      "idiomaDefecto" => "en"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "S157921291930045X"
          "doi" => "10.1016/j.arbr.2018.07.017"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => false
            "ES2" => false
            "LATM" => false
          ]
          "gratuito" => false
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157921291930045X?idApp=UINPBA00003Z"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289618303144?idApp=UINPBA00003Z"
      "url" => "/03002896/0000005500000003/v1_201903020650/S0300289618303144/v1_201903020650/en/main.assets"
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1579212918304506"
    "issn" => "15792129"
    "doi" => "10.1016/j.arbr.2018.12.018"
    "estado" => "S300"
    "fechaPublicacion" => "2019-03-01"
    "aid" => "1980"
    "copyright" => "SEPAR"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Arch Bronconeumol. 2019;55:134-8"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 482
      "formatos" => array:3 [
        "EPUB" => 40
        "HTML" => 327
        "PDF" => 115
      ]
    ]
    "en" => array:14 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>"
      "titulo" => "Lung Retransplantation Due to Chronic Lung Allograph Dysfunction&#58; Results From a Spanish Transplant Unit"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:3 [
        0 => "en"
        1 => "en"
        2 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "134"
          "paginaFinal" => "138"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Resultados del retrasplante pulmonar por disfunci&#243;n cr&#243;nica del injerto pulmonar en un centro trasplantador&#58; Hospital Vall D&#8217;Hebron de Barcelona"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 1
        "multimedia" => array:5 [
          "identificador" => "fig0005"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => false
          "mostrarDisplay" => true
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "fx1.jpeg"
              "Alto" => 987
              "Ancho" => 1333
              "Tamanyo" => 68712
            ]
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Eva Revilla-L&#243;pez, Cristina Berastegui, Berta S&#225;ez-Gim&#233;nez, Manuel Lopez-Meseguer, Victor Monforte, Carlos Bravo, Judith Sacanell Lacasa, Laura Romero Vielva, Antonio Moreno Galdo, Antonio Roman"
          "autores" => array:10 [
            0 => array:2 [
              "nombre" => "Eva"
              "apellidos" => "Revilla-L&#243;pez"
            ]
            1 => array:2 [
              "nombre" => "Cristina"
              "apellidos" => "Berastegui"
            ]
            2 => array:2 [
              "nombre" => "Berta"
              "apellidos" => "S&#225;ez-Gim&#233;nez"
            ]
            3 => array:2 [
              "nombre" => "Manuel"
              "apellidos" => "Lopez-Meseguer"
            ]
            4 => array:2 [
              "nombre" => "Victor"
              "apellidos" => "Monforte"
            ]
            5 => array:2 [
              "nombre" => "Carlos"
              "apellidos" => "Bravo"
            ]
            6 => array:2 [
              "nombre" => "Judith"
              "apellidos" => "Sacanell Lacasa"
            ]
            7 => array:2 [
              "nombre" => "Laura"
              "apellidos" => "Romero Vielva"
            ]
            8 => array:2 [
              "nombre" => "Antonio"
              "apellidos" => "Moreno Galdo"
            ]
            9 => array:2 [
              "nombre" => "Antonio"
              "apellidos" => "Roman"
            ]
          ]
        ]
      ]
      "resumen" => array:1 [
        0 => array:3 [
          "titulo" => "Graphical abstract"
          "clase" => "graphical"
          "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="fig0005"></elsevierMultimedia></p></span>"
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0300289618303181"
        "doi" => "10.1016/j.arbres.2018.07.025"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289618303181?idApp=UINPBA00003Z"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212918304506?idApp=UINPBA00003Z"
    "url" => "/15792129/0000005500000003/v1_201903020641/S1579212918304506/v1_201903020641/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S157921291830452X"
    "issn" => "15792129"
    "doi" => "10.1016/j.arbr.2018.08.001"
    "estado" => "S300"
    "fechaPublicacion" => "2019-03-01"
    "aid" => "1989"
    "copyright" => "SEPAR"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "sco"
    "cita" => "Arch Bronconeumol. 2019;55:126-7"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 345
      "formatos" => array:3 [
        "EPUB" => 39
        "HTML" => 217
        "PDF" => 89
      ]
    ]
    "en" => array:10 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>"
      "titulo" => "Treatment-Refractory Hypertension and Sleep Apnea&#46; One Step Further"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "126"
          "paginaFinal" => "127"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Hipertensi&#243;n refractaria al tratamiento y apnea del sue&#241;o&#46; Un paso m&#225;s all&#225;"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Miguel &#193;ngel Mart&#237;nez-Garc&#237;a, Francisco Campos-Rodriguez, Gerard Torres Cortada"
          "autores" => array:3 [
            0 => array:2 [
              "nombre" => "Miguel &#193;ngel"
              "apellidos" => "Mart&#237;nez-Garc&#237;a"
            ]
            1 => array:2 [
              "nombre" => "Francisco"
              "apellidos" => "Campos-Rodriguez"
            ]
            2 => array:2 [
              "nombre" => "Gerard"
              "apellidos" => "Torres Cortada"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0300289618303272"
        "doi" => "10.1016/j.arbres.2018.08.009"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289618303272?idApp=UINPBA00003Z"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157921291830452X?idApp=UINPBA00003Z"
    "url" => "/15792129/0000005500000003/v1_201903020641/S157921291830452X/v1_201903020641/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Association of <span class="elsevierStyleItalic">HTR2A</span>-1438G&#47;A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "128"
        "paginaFinal" => "133"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Zoraida Verde, Catalina Santiago, Luis M&#46; Chicharro, Fernando Bandr&#233;s, F&#233;lix G&#243;mez-Gallego, Jose Miguel Rodr&#237;guez Gonz&#225;lez-Moro, Pilar de Lucas"
        "autores" => array:7 [
          0 => array:4 [
            "nombre" => "Zoraida"
            "apellidos" => "Verde"
            "email" => array:1 [
              0 => "zoraida&#46;verde&#64;uva&#46;es"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Catalina"
            "apellidos" => "Santiago"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Luis M&#46;"
            "apellidos" => "Chicharro"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Fernando"
            "apellidos" => "Bandr&#233;s"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "F&#233;lix"
            "apellidos" => "G&#243;mez-Gallego"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">e</span>"
                "identificador" => "aff0025"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Jose Miguel"
            "apellidos" => "Rodr&#237;guez Gonz&#225;lez-Moro"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">f</span>"
                "identificador" => "aff0030"
              ]
            ]
          ]
          6 => array:3 [
            "nombre" => "Pilar"
            "apellidos" => "de Lucas"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">g</span>"
                "identificador" => "aff0035"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:7 [
          0 => array:3 [
            "entidad" => "Department of Biochemistry&#44; Molecular Biology and Physiology&#44; Universidad de Valladolid&#44; Soria&#44; Spain"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Department of Biomedical Sciences&#44; Universidad Europea&#44; Villaviciosa de Od&#243;n&#44; Madrid&#44; Spain"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "C&#225;tedra Complutense Diagnostic and Innovation&#44; Universidad Complutense&#44; Madrid&#44; Spain"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "Department of Toxicology and Health Sanitary&#44; Universidad Complutense&#44; Madrid&#44; Spain"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
          4 => array:3 [
            "entidad" => "School of Health Sciences&#44; Universidad Internacional de La Rioja&#44; Madrid&#44; Spain"
            "etiqueta" => "e"
            "identificador" => "aff0025"
          ]
          5 => array:3 [
            "entidad" => "Department of Neumology&#44; Hospital Universitario Pr&#237;ncipe de Asturias&#44; Alcal&#225; de Henares&#44; Madrid&#44; Spain"
            "etiqueta" => "f"
            "identificador" => "aff0030"
          ]
          6 => array:3 [
            "entidad" => "Department of Neumology&#44; Hospital General Universitario Gregorio Mara&#241;&#243;n&#44; Madrid&#44; Spain"
            "etiqueta" => "g"
            "identificador" => "aff0035"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Asociaci&#243;n del polimorfismo gen&#233;tico <span class="elsevierStyleItalic">HTR2A</span>-1438G&#47;A con el tabaco y la enfermedad pulmonar obstructiva cr&#243;nica"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 1
      "multimedia" => array:5 [
        "identificador" => "fig0005"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "fx1.jpeg"
            "Alto" => 354
            "Ancho" => 1333
            "Tamanyo" => 79499
          ]
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; is one of the leading causes of mortality and morbidity in the world&#46; Cigarette smoke has several deleterious effects on the airways&#44; leading to and&#47;or influencing chronic respiratory diseases such as COPD&#46; As only between 10 and 20&#37; of heavy smokers develop COPD&#44; risk of COPD depends on environmental and genetic factors&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The principal component of cigarettes is nicotine that acts at the central nervous system level&#44; causing changes in the brain of the smoker&#46; One of the principal effects of nicotine is the alteration of certain neurotransmitter levels&#44; including dopamine and serotonin &#40;5-hydroxytyptamine&#44; 5-HT&#41;&#46; Therefore&#44; the genes encoding the receptors or transporters involved in the dopaminergic and serotonergic pathways are potential candidates in the mechanisms of nicotine addiction&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In addition&#44; 5-HT is a neurotransmitter that plays an important role in pulmonary function&#46; Elevated levels of 5-HT are responsible for bronchoconstriction and pulmonary vasoconstriction and also increase the risk of risk of pulmonary hypertension &#40;PH&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">3&#8211;6</span></a> The development of PH in COPD is mainly attributed to alveolar hypoxia&#44; pulmonary vasoconstriction&#44; vessel remodeling and pulmonary vascular resistence&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The 5-HT transporter gene&#44; solute carrier family 6&#44; member 4 &#40;<span class="elsevierStyleItalic">SLC6A4</span>&#41; &#40;or 5-HT transporter&#58; 5-HTT&#41;&#44; is involved in 5-HT reuptake in the 5-HT pathway&#44; regulating plasma 5-HT levels&#44; and it is thought to be a good candidate for a genetic association with tobacco consumption and COPD&#46; Depression&#44; which is one of the important comorbidities of COPD&#44; is also associated to 5-HT levels and affects the quality of life&#44; exacerbations and mortality in these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;9</span></a> More recently&#44; Ishii and colleagues suggest that the quantity of cigarettes smoked may partially mediate the relation between <span class="elsevierStyleItalic">SLC6A4</span> genotypes and COPD pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> The activation of SLC6A4 on human airway epithelial cells regulates the release of interleukin-6 and interleukin-8 and could play a role in inflammatory responses of airway epithelial cells in COPD subjects by changing the concentration of 5-HT in the peripheral lungs&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">On the other hand&#44; the 5-hydroxytryptamine 2A receptor &#40;HTR2A&#41;&#44; encoded by <span class="elsevierStyleItalic">HTR2A</span> gene&#44; is a major post-synaptic target for 5-HT in the human brain and a therapeutic drug target&#46; 5-HT leads to pulmonary vasoconstriction via its 2A and B receptors&#46; Polymorphisms in HTR2A have been related to arterial hypertension or mood disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">12&#44;13</span></a> Very few studies have explored the association of SNPs in <span class="elsevierStyleItalic">HTR2A</span> gene with nicotine addiction and it has been published only one study in COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#8211;16</span></a> Functional studies have shown that the activation of 5-HT receptors stimulates different signaling pathways and regulates cytokine release in epithelial cells of the respiratory pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> Therefore&#44; increasing the risk of COPD&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Although the risk of cigarette smoking is well documented&#44; tobacco smoking continues to be the largest preventable cause of disease and premature death&#46; It is estimated that there are currently still over 1&#46;2 billion smokers worldwide&#44; and it is expected to reach about 1&#46;6&#8211;1&#46;9 billion by 2025&#46; According to the latest World Health Organization estimates by 2015 about 30&#37; of the smoking related deaths will probably be caused by chronic respiratory diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In Spain the prevalence of COPD in adult population is about 10&#46;2&#37; and in more than 30 pack years smoked smokers and older than 60 years is more than 40&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">18&#44;19</span></a> Therefore&#44; it is important to investigate possible predictors in order to prevent the disease at an early stage&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">On the basis of these previous findings&#44; the 5-HT system could contribute to the development of cigarette smoke-induced COPD&#46; The present study aimed at investigating the mediation effects of <span class="elsevierStyleItalic">SLC6A4 &#40;5HTT&#95;LPR&#41;</span> &#40;rs25531&#41; and <span class="elsevierStyleItalic">HTR2A-1438G&#47;A</span> &#40;rs6311&#41; genetic polymorphisms on the relation between smoking habits and COPD&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Material and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">An analytical&#44; case&#8211;control study was conducted&#46; This study followed the STREGA-guidelines &#40;STrengthening the REporting of Genetic Association Studies&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">COPD patients and healthy smokers&#44; reported more than 10 pack years smoked &#40;PY&#41;&#44; were randomly recruited in Hospital Gregorio Mara&#241;&#243;n Neumology Service&#46; All participants were active smokers&#46; The diagnosis of COPD was confirmed using spirometric criteria &#40;a postbronchodilation forced expiratory volume in the first second and forced vital capacity ratio &#40;FEV1&#47;FVC ratio&#41; less than 70&#37;&#41; at least 3 months after admission and with the patient in stable condition&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">All subjects were classified based on their consumption of cigarettes per day &#40;CPD&#41; and PY&#46; PY is a way to measure smoking intensity and is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked&#46; Body mass index &#40;BMI&#41; was taken as anthropometric measurement&#46; Spirometry Testing Airway function was measured at baseline in all study participants using a flow spirometer Spirolab II &#40;Medical International Research&#44; Rome&#44; Italy&#41; according to the guidelines of the European Respiratory Society &#40;ERS&#41;&#46; FEV1 and FVC values were expressed as a percentage of the predicted reference value according to the Spanish Society of Pulmonology and Thoracic Surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Blood samples were obtained by venipuncture and collected in tubes containing EDTA&#46; The DNA of the peripheral leukocytes was extracted using a standard phenol chloroform protocol&#46; DNA extraction and genotype analyses were carried out in the Biomedicine laboratory at the Universidad Europea&#44; Madrid &#40;Spain&#41;&#46; The study followed recommendations for replicating genotype-phenotype association studies&#44; genotyping was performed specifically for research purposes&#44; and researchers in charge of genotyping were totally blinded to the participants&#8217; identities &#40;blood and DNA samples were tracked solely with bar-coding and personal identities were only made available to the main study researcher who was not involved in actual genotyping&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> The DNA samples were stored at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C until analysis&#46; Genotyping was performed using an allele specific polymerase chain reaction as detailed elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The study protocol was approved by the institutional ethics committee &#40;Hospital Gregorio Mara&#241;&#243;n&#44; Madrid&#41;&#46; All patients provided written informed consent&#46; The study was in accordance with the Helsinki Declaration&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">All the values are expressed as mean &#40;SD&#41;&#46; We compared smoking phenotypes and clinical characteristics between the different groups with the unpaired Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#46; We used the <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test to assess deviations of genotype distributions from the Hardy-Weinberg equilibrium &#40;HWE&#41;&#46; We also used logistic regression to determine associations between smoking phenotypes and genotypes&#46; We compared genotypes and smoking phenotypes with ANOVA test&#46; All statistical analyses were corrected for multiple comparisons using the Bonferroni method&#44; in which the threshold <span class="elsevierStyleItalic">P</span>-value is obtained by dividing 0&#46;05 by the number of tests&#46; All analyses were performed with the SPSS Statistics 20&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41; program&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">167 patients were included in the study &#40;77 COPD patients and 90 healthy smokers&#41;&#46; The baseline characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The study participants smoked on average 39&#46;9 PY &#40;SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#46;9&#41;&#44; 56&#46;9&#37; of them were female and the overall mean age was 57 years &#40;SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">We analyzed the prevalence of the genetic polymorphisms <span class="elsevierStyleItalic">SLC6A4 &#40;5HTT&#95;LPR&#41;</span> &#40;rs25531&#41; and <span class="elsevierStyleItalic">HTR2A &#40;-1438A&#62;G&#41;</span> &#40;rs6311&#41; in COPD patients and healthy smokers&#46; No departure from Hardy-Weinberg equilibrium was detected for the genetic polymorphisms &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;697&#41; and &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;719&#41;&#44; respectively&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The distribution of <span class="elsevierStyleItalic">SLC6A4</span> genotypes did not vary between healthy smokers and COPD patients &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;758&#41;&#46; On the other hand&#44; we observed statistically significant differences between <span class="elsevierStyleItalic">HTR2A</span> genotypes and both groups &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41;&#46; Analyses focused on associations with genotype categorized using a recessive model &#40;i&#46;e&#46; homozygotes of the most common allele plus heterozygotes were the referent group&#44; compared to homozygotes of the minor allele&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The A allele of the SNP in <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; was significantly associated with COPD incidence in the trend model &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#59; 1&#46;80 &#40;1&#46;04&#8211;3&#46;11&#41;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Among all smokers&#44; this allele was also associated with the number of PY &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41; and we observed a marginal association with FEV1&#47;FVC values &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; After stratification&#44; we observed the same association in the group of COPD patients but not in the healthy smokers &#40;data not shown&#41;&#46; We didn&#8217;t find any relationship between genotype and gender or age <span class="elsevierStyleItalic">&#40;P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;351 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;116&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">No statistically relationship was observed between smoking habits or the clinical variables and <span class="elsevierStyleItalic">SLC6A4</span> &#40;rs25531&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">As expected&#44; we observed a correlation between PY as continuous variable and FEV1&#47;FVC&#44; FEV1&#37; and FVC&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;012 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#44; respectively&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">In our study we found a statistically significant relationship between the allele <span class="elsevierStyleItalic">A</span> of <span class="elsevierStyleItalic">HTR2A</span>-<span class="elsevierStyleItalic">1438G&#47;A</span> and COPD incidence&#46; Moreover&#44; we observed an association between this allele and PY or FEV1&#47;FVC&#44; however after stratification&#59; we only replicate the results in the COPD group&#46; These results could indicate that <span class="elsevierStyleItalic">HTR2A</span> variant affects COPD pathogenesis and this effect depends partly on tobacco consumption&#46; The acute effects of cigarette smoking produce central nervous system&#8211;mediated activation of the sympathetic nervous system&#46; The overactive sympathetic nervous system stimulates the secretion of serotonin &#40;5-HT&#41; and catecholamine into blood at supraphysiological levels&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a> Serotonin receptors variants in COPD patients could overactivate a cascade of inflammatory reactions induced by smoking&#46; Although preliminary&#44; the results of our study provide evidence that genetic variations in <span class="elsevierStyleItalic">HTR2A</span> may influence both smoking habits and the development of COPD&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">An association between <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; and smoking behavior has been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#44;25</span></a> In addition&#44; some authors have indicated an association of <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; with PH&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> However&#44; this is the first report on an association between <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; variant and COPD&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HTR2A</span> gene is located on chromosome 13q14-q21 and encodes a key membrane receptors of 5-HT&#46; 5-HT&#44; a biogenic amine&#44; is one of the principal neurotransmitters in the central nervous system&#44; interacts with a wide range of psychoactive compounds&#44; including nicotine&#44; and also acts as an important endocrine regulator&#44; playing a key role in the functioning of the cardiovascular and the respiratory system&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The activation of 5-HT receptors activates intracellular cascades that affect the functioning of other related systems &#40;glutamatergic&#44; dopaminegic&#44; and GABA-ergic&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> Functional studies showed that the activation of 5-HT receptors regulates the release of interleukin-6 and interleukin-8&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> It was also found that 5-HT stimulates different signaling pathways and regulates cytokine release in epithelial cells of the respiratory pathways&#59; thus&#44; it is involved in the pathogenesis of bronchial asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">On the other hand&#44; The <span class="elsevierStyleItalic">HTR2A</span> gene has been regarded as one of the potential candidates for susceptibility to smoking&#46; However&#44; it is not a major contributing factor&#46; The mesolimbic dopaminergic system mediates nicotine reinforcement in the brain&#44; and this system is modulated by the serotonergic system via HTR2A&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> Experimental models have shown that cigarette smoke inhibits monoamine oxidase &#40;MAO&#41; leading to higher levels of 5-HT&#46; Elevated levels of 5-HT are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The A allele of rs6311 increases promotor activity&#44; mRNA expression and protein levels and increases receptor binding&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">29&#44;30</span></a> This promoter polymorphism supports an hyperactive serotonergic system&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> In addition&#44; Falkerlber et al&#46; suggested that the promoter polymorphism &#40;rs6311&#41; can affect both transcription factor binding and promoter methylation&#44; and this along with an individual&#39;s stress response can impact the rate of <span class="elsevierStyleItalic">HTR2A</span> transcription in a genotype and methylation-dependent manner&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> The rs6311 polymorphism of <span class="elsevierStyleItalic">HTR2A</span> was previously shown to be associated with nicotine dependence and smoking behavior&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#44;25</span></a> However&#44; there is only one published study about rs6311 polymorphism of <span class="elsevierStyleItalic">HTR2A</span> and COPD risk and its results are not conclusive&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Way et al&#46; demonstrated the association between plasma 5-HT levels&#44; and COPD&#46; Higher plasma 5-HT levels were found in stable COPD patients compared to the control subjects&#46; An up-regulation of serotonergic pathway due to <span class="elsevierStyleItalic">HTR2A</span> genotype and smoking could be related to higher inflammatory response of airway epithelial cells and higher risk of COPD&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">On the other hand&#44; there were no differences between <span class="elsevierStyleItalic">SCL4A6</span> &#40;rs25531&#41; genotype and COPD&#46; There are no previous studies that analyzed <span class="elsevierStyleItalic">SLC4A6</span> &#40;rs25531&#41; polymorphism and COPD risk&#46; An association between <span class="elsevierStyleItalic">SCL4A6</span> &#40;rs2020936&#41; variant and smoking behavior or nicotine dependence has been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">15&#44;33</span></a> In addition&#44; Ishii and cols&#46; concluded that <span class="elsevierStyleItalic">SCL4A6</span> &#40;rs2020936&#41; variant affects COPD pathogenesis and depressive symptoms in Japanese population&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> It should be noted that in this study&#44; controls were a mixture of current and ex-smokers&#46; Other authors have reported that <span class="elsevierStyleItalic">SLC4A6</span> &#40;rs25531&#41; long allelic variant was associated with PH in COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> Ulrich et al&#46; supported a pathogenic role of the 5-HT system in the development of PH in COPD and the need for further studies in this field&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The present study has several limitations&#46; First&#44; a limitation of the current study is its relatively small sample size&#44; and as such&#44; the findings require replication&#46; To strengthen confidence in our findings we have selected an ethnically homogenous sample of Caucasians&#46; Second&#44; we have analyzed only two genetic variants of serotonin system genes&#46; Other different variants in the 5-HT signaling pathway&#44; such as described in tryptophan hydroxylase 2 &#40;<span class="elsevierStyleItalic">TPH2</span>&#41; and <span class="elsevierStyleItalic">MAO</span> type A&#44; could be related to the pathogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">On the other hand&#44; despite of the small simple size of the current study&#44; our population is homogeneous&#44; not stratified and well defined in terms of phenotype assessment and to our knowledge&#44; this is the first study to evaluate the relationship between smoking intensity&#44; COPD and the polymorphism <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; in Spanish population&#46; Moreover the study follows the STREGA guidelines&#44; all participants were randomly recruited in Hospital Gregorio Mara&#241;&#243;n Neumology Service by a pulmonary medicine specialist&#44; genetic polymorphisms were selected attending their prevalence and functional impact in the protein&#44; no departure from Hardy-Weinberg equilibrium was detected for the genetic polymorphisms or multiple testing and reporting of quantitative &#40;continuous&#41; outcomes were used&#41;&#46; Better reporting of studies facilitate the synthesis of available research results and the further development of study methods in genetic epidemiology improving the understanding of the role of genetic factors in the cause of diseases&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">Previous studies consider the hypothesis that&#44; in addition to their involvement in nicotine dependence&#44; 5-HT response in COPD patients could activate a cascade of inflammatory reactions induced by tobacco consumption&#46; We speculate that the cigarette smoke-mediated injury in COPD lungs is partially mediated by <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41;&#46; Despite the evidence that confer <span class="elsevierStyleItalic">SCL4A6</span> gene and 5-HT response we have not found any relationship between <span class="elsevierStyleItalic">SCL4A6</span> &#40;rs25531&#41; and COPD susceptibility&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">In summary&#44; although the effects of <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; alone are modest&#44; our results suggest a possible role of the A allele of rs6311 in COPD pathogenesis&#44; providing evidence that genetic variations in <span class="elsevierStyleItalic">HTR2A</span> may influence both&#44; smoking habits and the development of COPD&#46; Further investigation of the functional role and the regulation of 5-HT due to genetic variants in COPD is important for understanding and preventing the progression of this disease&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0165" class="elsevierStylePara elsevierViewall">This study was supported by a grant of SEPAR &#40;2006&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:15 [
        0 => array:3 [
          "identificador" => "xres1157950"
          "titulo" => "Graphical abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:3 [
          "identificador" => "xres1157948"
          "titulo" => "Abstract"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Introduction"
            ]
            1 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Objectives"
            ]
            2 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Methods"
            ]
            3 => array:2 [
              "identificador" => "abst0025"
              "titulo" => "Results"
            ]
            4 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Conclusion"
            ]
          ]
        ]
        2 => array:2 [
          "identificador" => "xpalclavsec1085056"
          "titulo" => "Keywords"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1085057"
          "titulo" => "Abbreviations"
        ]
        4 => array:3 [
          "identificador" => "xres1157949"
          "titulo" => "Resumen"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "abst0035"
              "titulo" => "Introducci&#243;n"
            ]
            1 => array:2 [
              "identificador" => "abst0040"
              "titulo" => "Objetivos"
            ]
            2 => array:2 [
              "identificador" => "abst0045"
              "titulo" => "M&#233;todos"
            ]
            3 => array:2 [
              "identificador" => "abst0050"
              "titulo" => "Resultados"
            ]
            4 => array:2 [
              "identificador" => "abst0055"
              "titulo" => "Conclusi&#243;n"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "xpalclavsec1085058"
          "titulo" => "Palabras clave"
        ]
        6 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        7 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Material and methods"
        ]
        8 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Statistical analysis"
        ]
        9 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Results"
        ]
        10 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Discussion"
        ]
        11 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Conclusions"
        ]
        12 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Funding"
        ]
        13 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conflict of interest"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-05-14"
    "fechaAceptado" => "2018-07-26"
    "PalabrasClave" => array:2 [
      "en" => array:2 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1085056"
          "palabras" => array:6 [
            0 => "Serotonin"
            1 => "<span class="elsevierStyleItalic">HTR2A</span>"
            2 => "<span class="elsevierStyleItalic">SLC6A4</span>"
            3 => "Smoking"
            4 => "Chronic obstructive pulmonary disease"
            5 => "Genetic polymorphisms"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1085057"
          "palabras" => array:13 [
            0 => "BMI"
            1 => "COPD"
            2 => "PH"
            3 => "ERS"
            4 => "FEV1"
            5 => "FVC"
            6 => "MAO"
            7 => "Serotonin"
            8 => "SLC6A4"
            9 => "STREGA"
            10 => "TPH2"
            11 => "HTR2A"
            12 => "5-HTT"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1085058"
          "palabras" => array:6 [
            0 => "Serotonina"
            1 => "<span class="elsevierStyleItalic">HTR2A</span>"
            2 => "<span class="elsevierStyleItalic">SLC6A4</span>"
            3 => "Consumo de tabaco"
            4 => "Enfermedad pulmonar obstructiva cr&#243;nica"
            5 => "Polimorfismos gen&#233;ticos"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cigarette smoking is a major risk factor in the development of chronic obstructive pulmonary disease &#40;COPD&#41;&#46; Serotonin levels have been associated with COPD and smoking has been as a significant modulator&#46; Elevated levels of serotonin are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence&#44; thus serotonin response could be affected by genetic polymorphisms in transporters and receptors of serotonin&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Objectives</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The aim of the current study was to analyze the effect of <span class="elsevierStyleItalic">SLC6A4</span> &#40;5HTT&#95;LPR&#41; &#40;rs25531&#41; and <span class="elsevierStyleItalic">HTR2A</span>-1438G&#47;A &#40;rs6311&#41; genetic polymorphisms on the relation between smoking habits and COPD&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The association between <span class="elsevierStyleItalic">SLC6A4</span> &#40;5HTT&#95;LPR&#41; &#40;rs25531&#41;&#44; <span class="elsevierStyleItalic">HTR2A</span>-1438G&#47;A &#40;rs6311&#41;&#44; smoking degree and COPD was analyzed in a total of 77 COPD patients &#40;active smokers&#41; and 90 control subjects &#40;active healthy smokers&#41;&#46; The DNA was extracted of peripheral leukocytes samples and genotyping was performed using an allele specific polymerase chain reaction&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Results</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The distribution of SLC6A4 genotypes did not vary between healthy smokers and COPD patients &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;758&#41;&#46; On the other hand&#44; the A allele of <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; was significantly associated with COPD incidence in the trend model &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#59; 1&#46;80 &#91;1&#46;04&#8211;3&#46;11&#93;&#41;&#46; Among all smokers&#44; this allele was also associated with the number of pack years smoked &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41; and also&#44; we observed a marginal association with FEV1&#47;FVC values &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusion</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Our results point a possible role of the A allele of <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; in COPD pathogenesis&#44; suggesting that this effect depends partly on tobacco consumption due to a gene-by-environment interaction&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Objectives"
          ]
          2 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Methods"
          ]
          3 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Results"
          ]
          4 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Conclusion"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introducci&#243;n</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El consumo de tabaco es el principal riesgo para desarrollar enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41;&#46; Los niveles de serotonina se han relacionado con el riesgo de desarrollo de EPOC&#44; siendo el consumo de tabaco un modulador significativo&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los niveles elevados de serotonina producen broncoconstricci&#243;n y vasoconstricci&#243;n pulmonar&#44; as&#237; como dependencia a la nicotina&#46; As&#237;&#44; la respuesta a serotonina podr&#237;a verse afectada por los polimorfismos gen&#233;ticos en los transportadores y receptores de este neurotransmisor&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Objetivos</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este estudio fue analizar el papel de los polimorfismos gen&#233;ticos <span class="elsevierStyleItalic">SLC6A4</span> &#40;5HTT&#95;LPR&#41; &#40;rs25531&#41; y <span class="elsevierStyleItalic">HTR2A</span> -1438G&#47;A &#40;rs6311&#41; en la relaci&#243;n entre el consumo de tabaco y la EPOC&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">M&#233;todos</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Se analiz&#243; la asociaci&#243;n entre <span class="elsevierStyleItalic">SLC6A4 &#40;5HTT&#95;LPR</span>&#41; &#40;rs25531&#41;&#44; <span class="elsevierStyleItalic">HTR2A -1438G&#47;A</span> &#40;rs6311&#41;&#44; grado de tabaquismo y EPOC en 77 pacientes con EPOC &#40;fumadores activos&#41; y 90 sujetos control &#40;fumadores activos sanos&#41;&#46; El ADN se extrajo a partir de leucocitos de sangre perif&#233;rica y la genotipificaci&#243;n se realiz&#243; utilizando la reacci&#243;n en cadena de la polimerasa alelo-espec&#237;fica&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Resultados</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">No se observaron diferencias en la distribuci&#243;n de genotipos SLC6A4 entre fumadores sanos y fumadores con EPOC &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;758&#41;&#46; Se encontr&#243; una asociaci&#243;n significativa entre el alelo A de <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; y la incidencia de EPOC en el modelo predictivo &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#59; 1&#44;80 &#91;1&#44;04-3&#44;11&#93;&#41;&#46; En los fumadores&#44; este alelo tambi&#233;n se asoci&#243; al n&#250;mero de paquetes fumados al a&#241;o &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#41; y&#44; adem&#225;s&#44; de forma marginal con los valores de FEV1&#47;FVC &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;06&#41;&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusi&#243;n</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados apuntan a un posible papel del alelo A de <span class="elsevierStyleItalic">HTR2A</span> &#40;rs6311&#41; en la patog&#233;nesis de EPOC&#44; indicando que este efecto depender&#237;a en parte del consumo de tabaco a trav&#233;s de una interacci&#243;n gen-ambiente&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Objetivos"
          ]
          2 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "M&#233;todos"
          ]
          3 => array:2 [
            "identificador" => "abst0050"
            "titulo" => "Resultados"
          ]
          4 => array:2 [
            "identificador" => "abst0055"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0180" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0050"
          ]
        ]
      ]
    ]
    "multimedia" => array:5 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Note</span>&#58; The values are given as mean &#40;SD&#41;&#46;</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; BMI&#44; Body mass index&#59; PY&#44; pack years smoked&#59; FEV1 &#40;&#37;&#41;&#44; forced expiratory volume in the first second&#59; FVC &#40;&#37;&#41;&#44; forced vital capacity&#59; COPD&#44; chronic obstructive pulmonary disease&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">All smokers &#40;167&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy smokers &#40;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">COPD smokers &#40;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57 &#40;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62 &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Females&#47;males &#40;number&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">95&#47;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&#47;57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#47;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#46;4 &#40;4&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#46;3 &#40;4&#46;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&#46;6 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#46;9 &#40;22&#46;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#46;2 &#40;16&#46;37&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#46;2 &#40;25&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEV1&#47;FVC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">72&#46;3 &#40;25&#46;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">88&#46;9 &#40;15&#46;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68&#46;1 &#40;25&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEV1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68&#46;8 &#40;19&#46;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">97&#46;3 &#40;19&#46;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">61&#46;7 &#40;28&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FVC&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">84&#46;2 &#40;21&#46;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&#46;1 &#40;18&#46;79&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&#46;3 &#40;19&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1977171.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Patients and healthy controls characteristics&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Note</span>&#58; The values are given as percentage&#46; Values bold if <span class="elsevierStyleItalic">P</span> value is &#60;0&#46;025&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; <span class="elsevierStyleItalic">SLC6A4</span>&#44; solute carrier family 6&#44; member 4&#59; <span class="elsevierStyleItalic">HTR2A</span>&#44; 5-hydroxytryptamine 2A receptor&#59; COPD&#44; chronic obstructive pulmonary disease&#59; OR&#44; overall risk for non-smokers&#59; CI confidence interval&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Significant <span class="elsevierStyleItalic">P</span> values &#40;&#60;0&#46;025&#41; are in bold&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Smokers</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">COPD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR &#40;95&#37;CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">SLC6A4 &#40;5HTT-LPR&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SS&#44; SL<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;437&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;09 &#40;0&#46;65&#8211;1&#46;85&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">HTR2A &#40;&#8722;1438A&#62;G&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AA&#44; AG<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;020</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;80 &#40;1&#46;04&#8211;3&#46;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1977172.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Reference genotype&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Genotypes between smokers groups&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Note</span>&#58; The values are given as mean &#40;SD&#41;&#46; Values bold if <span class="elsevierStyleItalic">P</span> value is &#60;0&#46;025&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; <span class="elsevierStyleItalic">SLC6A4</span>&#44; solute carrier family 6&#44; member 4&#59; <span class="elsevierStyleItalic">HTR2A</span>&#44; 5-hydroxytryptamine 2A receptor&#59; FEV1&#44; forced expiratory volume in the first second&#59; FVC&#44; forced vital capacity&#59; PY&#44; pack years smoked&#46;</p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Significant <span class="elsevierStyleItalic">P</span> values &#40;&#60;0&#46;025&#41; are in bold&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Total of smokers</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FEV1&#47;FEVC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FEV1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FVC&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">SLC6A4 &#40;5HTT-LPR&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SS&#44; SL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&#46;1 &#40;25&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67&#46;7 &#40;31&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&#46;8 &#40;22&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&#46;1 &#40;23&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78&#46;4 &#40;24&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71&#46;3 &#40;27&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">85&#46;6 &#40;17&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&#46;8 &#40;23&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;185&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;624&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;732&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;372&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">HTR2A &#40;&#8722;1438A&#62;G&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AA&#44; AG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">69&#46;7 &#40;25&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">66&#46;7 &#40;30&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&#46;6 &#40;20&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&#46;3 &#40;25&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">82&#46;2 &#40;22&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">77&#46;0 &#40;32&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87&#46;3 &#40;26&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&#46;3 &#40;14&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;061&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;194&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;519&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;024</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1977173.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">The association between genotypes&#44; phenotypes and smoking habits&#46;</p>"
        ]
      ]
      3 => array:5 [
        "identificador" => "upi0005"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.mp3"
          "ficheroTamanyo" => 3592872
        ]
      ]
      4 => array:5 [
        "identificador" => "fig0005"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "fx1.jpeg"
            "Alto" => 354
            "Ancho" => 1333
            "Tamanyo" => 79499
          ]
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:34 [
            0 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The 2014 Surgeon General&#39;s Report&#58; Commemorating the 50th Anniversary of the 1964 Report of the Advisory Committee to the US Surgeon General and Updating the Evidence on the Health Consequences of Cigarette Smoking"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46;J&#46; Alberg"
                            1 => "D&#46;R&#46; Shopland"
                            2 => "K&#46;M&#46; Cummings"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/aje/kwt335"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Epidemiol"
                        "fecha" => "2014"
                        "volumen" => "179"
                        "paginaInicial" => "403"
                        "paginaFinal" => "412"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24436362"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic variation as a predictor of smoking cessation success&#46; A promising preventive and intervention tool for chronic respiratory diseases&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Quaak"
                            1 => "C&#46;P&#46; Van Schayck"
                            2 => "A&#46;M&#46; Knaapen"
                            3 => "F&#46;J&#46; Van Schooten"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.00056908"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2009"
                        "volumen" => "33"
                        "paginaInicial" => "468"
                        "paginaFinal" => "480"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19251795"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic polymorphisms of the serotonin transporter&#44; but not the 2a receptor or nitric oxide synthetase&#44; are associated with pulmonary hypertension in chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Ulrich"
                            1 => "M&#46; Hersberger"
                            2 => "M&#46; Fischler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000226243"
                      "Revista" => array:5 [
                        "tituloSerie" => "Respiration"
                        "fecha" => "2010"
                        "volumen" => "79"
                        "paginaInicial" => "288"
                        "paginaFinal" => "295"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Eddahibi"
                            1 => "A&#46; Chaouat"
                            2 => "N&#46; Morrell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.CIR.0000091409.53101.E8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2003"
                        "volumen" => "108"
                        "paginaInicial" => "1839"
                        "paginaFinal" => "1844"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14530202"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of circulating serotonin in the development of chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "W&#46;K&#46;W&#46; Lau"
                            1 => "M&#46;M&#46;W&#46; Chan-Yeung"
                            2 => "B&#46;H&#46;K&#46; Yip"
                            3 => "A&#46;H&#46;K&#46; Cheung"
                            4 => "M&#46;S&#46;M&#46; Ip"
                            5 => "J&#46;C&#46;W&#46; Mak"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0031617"
                      "Revista" => array:5 [
                        "tituloSerie" => "PLoS ONE"
                        "fecha" => "2012"
                        "volumen" => "7"
                        "paginaInicial" => "e31617"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22319639"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "I&#46; Morecroft"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1124/jpet.104.081182"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pharmacol Exp Ther"
                        "fecha" => "2004"
                        "volumen" => "313"
                        "paginaInicial" => "539"
                        "paginaFinal" => "548"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15659538"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary hypertension in chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;A&#46; Barbera"
                            1 => "V&#46;I&#46; Peinado"
                            2 => "S&#46; Santos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.03.00115402"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2003"
                        "volumen" => "21"
                        "paginaInicial" => "892"
                        "paginaFinal" => "905"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12765440"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Systemic manifestations and comorbidities of COPD"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46;J&#46; Barnes"
                            1 => "B&#46;R&#46; Celli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.00128008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2009"
                        "volumen" => "33"
                        "paginaInicial" => "1165"
                        "paginaFinal" => "1185"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19407051"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Independent effect of depression and anxiety on chronic obstructive pulmonary disease exacerbations and hospitalizations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "W&#46; Xu"
                            1 => "J&#46; Collet"
                            2 => "S&#46; Shapiro"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200804-619OC"
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2008"
                        "volumen" => "178"
                        "paginaInicial" => "913"
                        "paginaFinal" => "920"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of serotonin transporter gene variation with smoking&#44; chronic obstructive pulmonary disease&#44; and its depressive symptoms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "T&#46; Ishii"
                            1 => "R&#46; Wakabayashi"
                            2 => "H&#46; Kurosaki"
                            3 => "A&#46; Gemma"
                            4 => "K&#46; Kida"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/jhg.2010.133"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hum Genet"
                        "fecha" => "2011"
                        "volumen" => "56"
                        "paginaInicial" => "41"
                        "paginaFinal" => "46"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20981038"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serotoninergic receptors on human airway epithelial cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "H&#46; Bayer"
                            1 => "T&#46; M&#252;ller"
                            2 => "D&#46; Myrtek"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1165/rcmb.2006-0151OC"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2007"
                        "volumen" => "36"
                        "paginaInicial" => "85"
                        "paginaFinal" => "93"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16873768"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association study of the 5-HT&#40;2A&#41; receptor gene polymorphism&#44; T102C and essential hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46; Liolitsa"
                            1 => "J&#46;F&#46; Powell"
                            2 => "M&#46; Prince"
                            3 => "S&#46; Lovestone"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.jhh.1001177"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hum Hypertens"
                        "fecha" => "2001"
                        "volumen" => "15"
                        "paginaInicial" => "335"
                        "paginaFinal" => "339"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11378836"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "S0021915099003561 &#91;pii&#93;"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "T102C polymorphism of the serotonin &#40;5-HT&#41; 2A receptor gene in patients with non-fatal acute myocardial infarction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Yamada"
                            1 => "H&#46; Akita"
                            2 => "K&#46; Kanazawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Atherosclerosis"
                        "fecha" => "2000"
                        "volumen" => "150"
                        "paginaInicial" => "143"
                        "paginaFinal" => "148"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10781645"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms in HTR2A and DRD4 predispose to smoking and smoking quantity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "G&#46; P&#233;rez-Rubio"
                            1 => "A&#46; Ram&#237;rez-Venegas"
                            2 => "V&#46;N&#46; D&#237;az"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0170019"
                      "Revista" => array:3 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2017"
                        "volumen" => "12"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#8220;Smoking Genes&#8221;&#58; a genetic association study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "Z&#46; Verde"
                            1 => "C&#46; Santiago"
                            2 => "J&#46;M&#46;R&#46; Gonz&#225;lez-Moro"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0026668"
                      "Revista" => array:4 [
                        "tituloSerie" => "PLOS ONE"
                        "fecha" => "2011"
                        "volumen" => "6"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22162769"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphic variants of glutamate receptor &#40;GRIK5&#44; GRIN2B&#41; and serotonin receptor &#40;HTR2A&#41; genes are associated with chronic obstructive pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46;F&#46; Korytina"
                            1 => "L&#46;Z&#46; Akhmadishina"
                            2 => "O&#46;V&#46; Kochetova"
                            3 => "Y&#46;G&#46; Aznabaeva"
                            4 => "S&#46;Z&#46; Zagidullin"
                            5 => "T&#46;V&#46; Victorova"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7868/S0026898417040127"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Biol &#40;Mosk&#41;"
                        "fecha" => "2017"
                        "volumen" => "51"
                        "paginaInicial" => "603"
                        "paginaFinal" => "614"
                        "itemHostRev" => array:3 [
                          "pii" => "S1470204513700482"
                          "estado" => "S300"
                          "issn" => "14702045"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "doi&#58;978 92 4 156492 2"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "WHO global report on trends in prevalence of tobacco smoking 2015"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "World Health Organization"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "WHO Mag"
                        "fecha" => "2015"
                        "paginaInicial" => "1"
                        "paginaFinal" => "359"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of chronic obstructive pulmonary disease and risk factors in smokers and ex-smokers"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;I&#46; Ja&#233;n D&#237;az"
                            1 => "C&#46; de Castro Mesa"
                            2 => "M&#46;J&#46; Gont&#225;n Garc&#237;a-Salamanca"
                            3 => "F&#46; L&#243;pez de Castro"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2003"
                        "volumen" => "39"
                        "paginaInicial" => "554"
                        "paginaFinal" => "558"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14636492"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estudio EPI-SCAN&#58; resumen del protocolo de un estudio para estimar la prevalencia de EPOC en personas de 40 a 80 a&#241;os en Espa&#241;a"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46; Ancochea"
                            1 => "C&#46; Badiola"
                            2 => "E&#46; Duran-Tauleria"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2008.06.001"
                      "Revista" => array:5 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2009"
                        "volumen" => "45"
                        "paginaInicial" => "41"
                        "paginaFinal" => "47"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "STrengthening the REporting of genetic association studies &#40;STREGA&#41; &#8211; an extension of the STROBE statement"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46; Little"
                            1 => "J&#46;P&#46;T&#46; Higgins"
                            2 => "J&#46;P&#46;A&#46; Ioannidis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/gepi.20410"
                      "Revista" => array:6 [
                        "tituloSerie" => "Genet Epidemiol"
                        "fecha" => "2009"
                        "volumen" => "33"
                        "paginaInicial" => "581"
                        "paginaFinal" => "598"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19278015"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Standards for the diagnosis and treatment of patients with COPD&#58; a summary of the ATS&#47;ERS position paper"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "B&#46;R&#46; Celli"
                            1 => "W&#46; MacNee"
                            2 => "A&#46; Agusti"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.04.00014304"
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2004"
                        "volumen" => "23"
                        "paginaInicial" => "932"
                        "paginaFinal" => "946"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spirometry&#46; Spanish Society of Pulmonology and Thoracic Surgery &#40;SEPAR&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "F&#46; Garc&#237;a-R&#237;o"
                            1 => "M&#46; Calle"
                            2 => "F&#46; Burgos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2013.04.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2013"
                        "volumen" => "49"
                        "paginaInicial" => "388"
                        "paginaFinal" => "401"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23726118"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Replicating genotype-phenotype associations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46;J&#46; Chanock"
                            1 => "T&#46; Manolio"
                            2 => "M&#46; Boehnke"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/447655a"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "2007"
                        "volumen" => "447"
                        "paginaInicial" => "655"
                        "paginaFinal" => "660"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17554299"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "<a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="http://www.ncbi.nlm.nih.gov/pubmed/6614213">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed&#47;6614213</a>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential pattern of sympathetic outflow during upper airway stimulation with smoke"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46;F&#46; Peterson"
                            1 => "J&#46;H&#46; Coote"
                            2 => "M&#46;P&#46; Gilbey"
                            3 => "H&#46;A&#46; Futuro-Neto"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajpregu.1983.245.3.R433"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1983"
                        "volumen" => "245"
                        "paginaInicial" => "R433"
                        "paginaFinal" => "R437"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6614213"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Are serotonergic system genes associated to smoking cessation therapy success in addition to CYP2A6&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "Z&#46; Verde"
                            1 => "C&#46; Santiago"
                            2 => "J&#46; Rodr&#237;guez Gonz&#225;lez-Moro"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0033-1358393"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacopsychiatry"
                        "fecha" => "2014"
                        "volumen" => "47"
                        "paginaInicial" => "33"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24127329"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serotonin receptor gene &#40;HTR2A&#41; T102C polymorphism modulates individuals&#8217; perspective taking ability and autistic-like traits"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46; Gong"
                            1 => "J&#46; Liu"
                            2 => "P&#46;R&#46; Blue"
                            3 => "S&#46; Li"
                            4 => "X&#46; Zhou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fnhum.2015.00575"
                      "Revista" => array:3 [
                        "tituloSerie" => "Front Hum Neurosci"
                        "fecha" => "2015"
                        "volumen" => "9"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association and interaction analyses of 5-HT3 receptor and serotonin transporter genes with alcohol&#44; cocaine&#44; and nicotine dependence using the SAGE data"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Yang"
                            1 => "M&#46;D&#46; Li"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00439-014-1431-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hum Genet"
                        "fecha" => "2014"
                        "volumen" => "133"
                        "paginaInicial" => "905"
                        "paginaFinal" => "918"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24590108"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reciprocal autoreceptor and heteroreceptor control of serotonergic&#44; dopaminergic and noradrenergic transmission in the frontal cortex&#58; relevance to the actions of antidepressant agents"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;J&#46; Millan"
                            1 => "F&#46; Lejeune"
                            2 => "A&#46; Gobert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/026988110001400202"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Psychopharmacol"
                        "fecha" => "2000"
                        "volumen" => "14"
                        "paginaInicial" => "114"
                        "paginaFinal" => "138"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10890307"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "&#91;pii&#93;"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential expression of the &#8220;C&#8221; and &#8220;T&#8221; alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "O&#46;O&#46; Polesskaya"
                            1 => "B&#46;P&#46; Sokolov"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jnr.10173"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurosci Res"
                        "fecha" => "2002"
                        "volumen" => "67"
                        "paginaInicial" => "812"
                        "paginaFinal" => "822"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11891796"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "G&#46; Turecki"
                            1 => "R&#46; Bri&#232;re"
                            2 => "K&#46; Dewar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1176/ajp.156.9.1456"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Psychiatry"
                        "fecha" => "1999"
                        "volumen" => "156"
                        "paginaInicial" => "1456"
                        "paginaFinal" => "1458"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10484964"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "<a class="elsevierStyleInterRef" target="_blank" id="intr0015" href="http://www.embase.com/search/results?subaction=viewrecord%26from=export%26id=L40187367%5Cnhttps://doi.org/10.1016/j.biopsych.2004.10.031%5Cnhttp://openurl.ac.uk/ukfed:bath.ac.uk?sid=EMBASE%26issn=00063223%26id=doi:10.1016%2Fj.biopsych.2004.10.031%26atitle=Brain+5">http&#58;&#47;&#47;www&#46;embase&#46;com&#47;search&#47;results&#63;subaction&#61;viewrecord&#38;from&#61;export&#38;id&#61;L40187367&#37;5Cnhttps&#58;&#47;&#47;doi&#46;org&#47;10&#46;1016&#47;j&#46;biopsych&#46;2004&#46;10&#46;031&#37;5Cnhttp&#58;&#47;&#47;openurl&#46;ac&#46;uk&#47;ukfed&#58;bath&#46;ac&#46;uk&#63;sid&#61;EMBASE&#38;issn&#61;00063223&#38;id&#61;doi&#58;10&#46;1016&#37;2Fj&#46;biopsych&#46;2004&#46;10&#46;031&#38;atitle&#61;Brain&#43;5</a>"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and &#91;11C&#93;WAY-100635"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;J&#46; Cleare"
                            1 => "C&#46; Messa"
                            2 => "E&#46;A&#46; Rabiner"
                            3 => "P&#46;M&#46; Grasby"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.biopsych.2004.10.031"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biol Psychiatry"
                        "fecha" => "2005"
                        "volumen" => "57"
                        "paginaInicial" => "239"
                        "paginaFinal" => "246"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15691524"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional genomics of serotonin receptor 2A &#40;HTR2A&#41;&#58; interaction of polymorphism&#44; methylation&#44; expression and disease association"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "V&#46;R&#46; Falkenberg"
                            1 => "B&#46;M&#46; Gurbaxani"
                            2 => "E&#46;R&#46; Unger"
                            3 => "M&#46;S&#46; Rajeevan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12017-010-8138-2"
                      "Revista" => array:5 [
                        "tituloSerie" => "NeuroMol Med"
                        "fecha" => "2011"
                        "volumen" => "13"
                        "paginaInicial" => "66"
                        "paginaFinal" => "76"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between 5-hydroxytryptamine transporter gene-linked polymorphic region and smoking behavior in Chinese males"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S&#46;L&#46; Chu"
                            1 => "X&#46; Dan"
                            2 => "W&#46; Chen"
                            3 => "J&#46; Hang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3760/cma.j.issn.0366-6999.2009.12.002"
                      "Revista" => array:5 [
                        "tituloSerie" => "Chin Med J &#40;Engl&#41;"
                        "fecha" => "2009"
                        "volumen" => "122"
                        "paginaInicial" => "1365"
                        "paginaFinal" => "1368"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tryptophan hydroxylase 2 &#40;TPH2&#41; haplotypes predict levels of TPH2 mRNA expression in human pons"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;E&#46; Lim"
                            1 => "J&#46; Pinsonneault"
                            2 => "W&#46; Sadee"
                            3 => "D&#46; Saffen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.mp.4001923"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Psychiatry"
                        "fecha" => "2007"
                        "volumen" => "12"
                        "paginaInicial" => "491"
                        "paginaFinal" => "501"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17453063"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/15792129/0000005500000003/v1_201903020641/S157921291930045X/v1_201903020641/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "9374"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original Articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005500000003/v1_201903020641/S157921291930045X/v1_201903020641/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157921291930045X?idApp=UINPBA00003Z"
]
Share
Journal Information
Vol. 55. Issue 3.
Pages 128-133 (March 2019)
Share
Share
Download PDF
More article options
Visits
3427
Vol. 55. Issue 3.
Pages 128-133 (March 2019)
Original article
Full text access
Association of HTR2A-1438G/A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease
Asociación del polimorfismo genético HTR2A-1438G/A con el tabaco y la enfermedad pulmonar obstructiva crónica
Visits
3427
Zoraida Verdea,
Corresponding author
zoraida.verde@uva.es

Corresponding author.
, Catalina Santiagob, Luis M. Chicharroc, Fernando Bandrésd, Félix Gómez-Gallegoe, Jose Miguel Rodríguez González-Morof, Pilar de Lucasg
a Department of Biochemistry, Molecular Biology and Physiology, Universidad de Valladolid, Soria, Spain
b Department of Biomedical Sciences, Universidad Europea, Villaviciosa de Odón, Madrid, Spain
c Cátedra Complutense Diagnostic and Innovation, Universidad Complutense, Madrid, Spain
d Department of Toxicology and Health Sanitary, Universidad Complutense, Madrid, Spain
e School of Health Sciences, Universidad Internacional de La Rioja, Madrid, Spain
f Department of Neumology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
g Department of Neumology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Podcast
This item has received
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Tables (3)
Table 1. Patients and healthy controls characteristics.
Table 2. Genotypes between smokers groups.
Table 3. The association between genotypes, phenotypes and smoking habits.
Show moreShow less
Additional material (1)
Figures (1)
Abstract
Introduction

Cigarette smoking is a major risk factor in the development of chronic obstructive pulmonary disease (COPD). Serotonin levels have been associated with COPD and smoking has been as a significant modulator. Elevated levels of serotonin are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence, thus serotonin response could be affected by genetic polymorphisms in transporters and receptors of serotonin.

Objectives

The aim of the current study was to analyze the effect of SLC6A4 (5HTT_LPR) (rs25531) and HTR2A-1438G/A (rs6311) genetic polymorphisms on the relation between smoking habits and COPD.

Methods

The association between SLC6A4 (5HTT_LPR) (rs25531), HTR2A-1438G/A (rs6311), smoking degree and COPD was analyzed in a total of 77 COPD patients (active smokers) and 90 control subjects (active healthy smokers). The DNA was extracted of peripheral leukocytes samples and genotyping was performed using an allele specific polymerase chain reaction.

Results

The distribution of SLC6A4 genotypes did not vary between healthy smokers and COPD patients (P=0.758). On the other hand, the A allele of HTR2A (rs6311) was significantly associated with COPD incidence in the trend model (P=0.02; 1.80 [1.04–3.11]). Among all smokers, this allele was also associated with the number of pack years smoked (P=0.02) and also, we observed a marginal association with FEV1/FVC values (P=0.06).

Conclusion

Our results point a possible role of the A allele of HTR2A (rs6311) in COPD pathogenesis, suggesting that this effect depends partly on tobacco consumption due to a gene-by-environment interaction.

Keywords:
Serotonin
HTR2A
SLC6A4
Smoking
Chronic obstructive pulmonary disease
Genetic polymorphisms
Abbreviations:
BMI
COPD
PH
ERS
FEV1
FVC
MAO
Serotonin
SLC6A4
STREGA
TPH2
HTR2A
5-HTT
Resumen
Introducción

El consumo de tabaco es el principal riesgo para desarrollar enfermedad pulmonar obstructiva crónica (EPOC). Los niveles de serotonina se han relacionado con el riesgo de desarrollo de EPOC, siendo el consumo de tabaco un modulador significativo.

Los niveles elevados de serotonina producen broncoconstricción y vasoconstricción pulmonar, así como dependencia a la nicotina. Así, la respuesta a serotonina podría verse afectada por los polimorfismos genéticos en los transportadores y receptores de este neurotransmisor.

Objetivos

El objetivo de este estudio fue analizar el papel de los polimorfismos genéticos SLC6A4 (5HTT_LPR) (rs25531) y HTR2A -1438G/A (rs6311) en la relación entre el consumo de tabaco y la EPOC.

Métodos

Se analizó la asociación entre SLC6A4 (5HTT_LPR) (rs25531), HTR2A -1438G/A (rs6311), grado de tabaquismo y EPOC en 77 pacientes con EPOC (fumadores activos) y 90 sujetos control (fumadores activos sanos). El ADN se extrajo a partir de leucocitos de sangre periférica y la genotipificación se realizó utilizando la reacción en cadena de la polimerasa alelo-específica.

Resultados

No se observaron diferencias en la distribución de genotipos SLC6A4 entre fumadores sanos y fumadores con EPOC (p=0,758). Se encontró una asociación significativa entre el alelo A de HTR2A (rs6311) y la incidencia de EPOC en el modelo predictivo (p=0,02; 1,80 [1,04-3,11]). En los fumadores, este alelo también se asoció al número de paquetes fumados al año (p=0,02) y, además, de forma marginal con los valores de FEV1/FVC (p=0,06).

Conclusión

Nuestros resultados apuntan a un posible papel del alelo A de HTR2A (rs6311) en la patogénesis de EPOC, indicando que este efecto dependería en parte del consumo de tabaco a través de una interacción gen-ambiente.

Palabras clave:
Serotonina
HTR2A
SLC6A4
Consumo de tabaco
Enfermedad pulmonar obstructiva crónica
Polimorfismos genéticos
Full Text
Introduction

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and morbidity in the world. Cigarette smoke has several deleterious effects on the airways, leading to and/or influencing chronic respiratory diseases such as COPD. As only between 10 and 20% of heavy smokers develop COPD, risk of COPD depends on environmental and genetic factors.1

The principal component of cigarettes is nicotine that acts at the central nervous system level, causing changes in the brain of the smoker. One of the principal effects of nicotine is the alteration of certain neurotransmitter levels, including dopamine and serotonin (5-hydroxytyptamine, 5-HT). Therefore, the genes encoding the receptors or transporters involved in the dopaminergic and serotonergic pathways are potential candidates in the mechanisms of nicotine addiction.2

In addition, 5-HT is a neurotransmitter that plays an important role in pulmonary function. Elevated levels of 5-HT are responsible for bronchoconstriction and pulmonary vasoconstriction and also increase the risk of risk of pulmonary hypertension (PH).3–6 The development of PH in COPD is mainly attributed to alveolar hypoxia, pulmonary vasoconstriction, vessel remodeling and pulmonary vascular resistence.7

The 5-HT transporter gene, solute carrier family 6, member 4 (SLC6A4) (or 5-HT transporter: 5-HTT), is involved in 5-HT reuptake in the 5-HT pathway, regulating plasma 5-HT levels, and it is thought to be a good candidate for a genetic association with tobacco consumption and COPD. Depression, which is one of the important comorbidities of COPD, is also associated to 5-HT levels and affects the quality of life, exacerbations and mortality in these patients.8,9 More recently, Ishii and colleagues suggest that the quantity of cigarettes smoked may partially mediate the relation between SLC6A4 genotypes and COPD pathogenesis.10 The activation of SLC6A4 on human airway epithelial cells regulates the release of interleukin-6 and interleukin-8 and could play a role in inflammatory responses of airway epithelial cells in COPD subjects by changing the concentration of 5-HT in the peripheral lungs.11

On the other hand, the 5-hydroxytryptamine 2A receptor (HTR2A), encoded by HTR2A gene, is a major post-synaptic target for 5-HT in the human brain and a therapeutic drug target. 5-HT leads to pulmonary vasoconstriction via its 2A and B receptors. Polymorphisms in HTR2A have been related to arterial hypertension or mood disorders.12,13 Very few studies have explored the association of SNPs in HTR2A gene with nicotine addiction and it has been published only one study in COPD.14–16 Functional studies have shown that the activation of 5-HT receptors stimulates different signaling pathways and regulates cytokine release in epithelial cells of the respiratory pathways.11 Therefore, increasing the risk of COPD.

Although the risk of cigarette smoking is well documented, tobacco smoking continues to be the largest preventable cause of disease and premature death. It is estimated that there are currently still over 1.2 billion smokers worldwide, and it is expected to reach about 1.6–1.9 billion by 2025. According to the latest World Health Organization estimates by 2015 about 30% of the smoking related deaths will probably be caused by chronic respiratory diseases.17

In Spain the prevalence of COPD in adult population is about 10.2% and in more than 30 pack years smoked smokers and older than 60 years is more than 40%.18,19 Therefore, it is important to investigate possible predictors in order to prevent the disease at an early stage.

On the basis of these previous findings, the 5-HT system could contribute to the development of cigarette smoke-induced COPD. The present study aimed at investigating the mediation effects of SLC6A4 (5HTT_LPR) (rs25531) and HTR2A-1438G/A (rs6311) genetic polymorphisms on the relation between smoking habits and COPD.

Material and methods

An analytical, case–control study was conducted. This study followed the STREGA-guidelines (STrengthening the REporting of Genetic Association Studies).20

COPD patients and healthy smokers, reported more than 10 pack years smoked (PY), were randomly recruited in Hospital Gregorio Marañón Neumology Service. All participants were active smokers. The diagnosis of COPD was confirmed using spirometric criteria (a postbronchodilation forced expiratory volume in the first second and forced vital capacity ratio (FEV1/FVC ratio) less than 70%) at least 3 months after admission and with the patient in stable condition.21

All subjects were classified based on their consumption of cigarettes per day (CPD) and PY. PY is a way to measure smoking intensity and is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked. Body mass index (BMI) was taken as anthropometric measurement. Spirometry Testing Airway function was measured at baseline in all study participants using a flow spirometer Spirolab II (Medical International Research, Rome, Italy) according to the guidelines of the European Respiratory Society (ERS). FEV1 and FVC values were expressed as a percentage of the predicted reference value according to the Spanish Society of Pulmonology and Thoracic Surgery.22

Blood samples were obtained by venipuncture and collected in tubes containing EDTA. The DNA of the peripheral leukocytes was extracted using a standard phenol chloroform protocol. DNA extraction and genotype analyses were carried out in the Biomedicine laboratory at the Universidad Europea, Madrid (Spain). The study followed recommendations for replicating genotype-phenotype association studies, genotyping was performed specifically for research purposes, and researchers in charge of genotyping were totally blinded to the participants’ identities (blood and DNA samples were tracked solely with bar-coding and personal identities were only made available to the main study researcher who was not involved in actual genotyping).23 The DNA samples were stored at −20°C until analysis. Genotyping was performed using an allele specific polymerase chain reaction as detailed elsewhere.15

The study protocol was approved by the institutional ethics committee (Hospital Gregorio Marañón, Madrid). All patients provided written informed consent. The study was in accordance with the Helsinki Declaration.

Statistical analysis

All the values are expressed as mean (SD). We compared smoking phenotypes and clinical characteristics between the different groups with the unpaired Student's t-test. We used the χ2 test to assess deviations of genotype distributions from the Hardy-Weinberg equilibrium (HWE). We also used logistic regression to determine associations between smoking phenotypes and genotypes. We compared genotypes and smoking phenotypes with ANOVA test. All statistical analyses were corrected for multiple comparisons using the Bonferroni method, in which the threshold P-value is obtained by dividing 0.05 by the number of tests. All analyses were performed with the SPSS Statistics 20.0 (SPSS Inc., Chicago, IL, USA) program.

Results

167 patients were included in the study (77 COPD patients and 90 healthy smokers). The baseline characteristics of the patients are shown in Table 1. The study participants smoked on average 39.9 PY (SD=22.9), 56.9% of them were female and the overall mean age was 57 years (SD=13).

Table 1.

Patients and healthy controls characteristics.

  All smokers (167)  Healthy smokers (90)  COPD smokers (77) 
Age (years)  57 (13)  49 (12)  62 (10) 
Females/males (number)  95/72  33/57  62/15 
BMI  26.4 (4.6)  25.3 (4.22)  27.6 (4.8) 
PY  39.9 (22.99)  31.2 (16.37)  50.2 (25.4) 
FEV1/FVC  72.3 (25.31)  88.9 (15.48)  68.1 (25.6) 
FEV1%  68.8 (19.27)  97.3 (19.27)  61.7 (28.2) 
FVC%  84.2 (21.15)  100.1 (18.79)  80.3 (19.9) 

Note: The values are given as mean (SD).

Abbreviations: BMI, Body mass index; PY, pack years smoked; FEV1 (%), forced expiratory volume in the first second; FVC (%), forced vital capacity; COPD, chronic obstructive pulmonary disease.

We analyzed the prevalence of the genetic polymorphisms SLC6A4 (5HTT_LPR) (rs25531) and HTR2A (-1438A>G) (rs6311) in COPD patients and healthy smokers. No departure from Hardy-Weinberg equilibrium was detected for the genetic polymorphisms (P=0.697) and (P=0.719), respectively.

The distribution of SLC6A4 genotypes did not vary between healthy smokers and COPD patients (P=0.758). On the other hand, we observed statistically significant differences between HTR2A genotypes and both groups (P=0.037). Analyses focused on associations with genotype categorized using a recessive model (i.e. homozygotes of the most common allele plus heterozygotes were the referent group, compared to homozygotes of the minor allele).

The A allele of the SNP in HTR2A (rs6311) was significantly associated with COPD incidence in the trend model (P=0.02; 1.80 (1.04–3.11)) (Table 2). Among all smokers, this allele was also associated with the number of PY (P=0.02) and we observed a marginal association with FEV1/FVC values (P=0.06) (Table 3). After stratification, we observed the same association in the group of COPD patients but not in the healthy smokers (data not shown). We didn’t find any relationship between genotype and gender or age (P=0.351 and P=0.116, respectively).

Table 2.

Genotypes between smokers groups.

  Smokers
  Healthy  COPD  P  OR (95%CI) 
SLC6A4 (5HTT-LPR)
SS, SLa  73.3  75.7  0.437  1.09 (0.65–1.85) 
LL  26.7  24.3     
HTR2A (−1438A>G)
AA, AGa  64.4  80.3  0.020  1.80 (1.04–3.11) 
GG  35.6  19.7     

Note: The values are given as percentage. Values bold if P value is <0.025.

Abbreviations: SLC6A4, solute carrier family 6, member 4; HTR2A, 5-hydroxytryptamine 2A receptor; COPD, chronic obstructive pulmonary disease; OR, overall risk for non-smokers; CI confidence interval.

Significant P values (<0.025) are in bold.

a

Reference genotype.

Table 3.

The association between genotypes, phenotypes and smoking habits.

  Total of smokers
  FEV1/FEVC  FEV1%  FVC%  PY 
SLC6A4 (5HTT-LPR)
SS, SL  70.1 (25.6)  67.7 (31.7)  83.8 (22.7)  39.1 (23.2) 
LL  78.4 (24.5)  71.3 (27.0)  85.6 (17.0)  42.8 (23.0) 
P  0.185  0.624  0.732  0.372 
HTR2A (−1438A>G)
AA, AG  69.7 (25.5)  66.7 (30.1)  83.6 (20.5)  42.3 (25.3) 
GG  82.2 (22.4)  77.0 (32.0)  87.3 (26.6)  33.3 (14.0) 
P  0.061  0.194  0.519  0.024 

Note: The values are given as mean (SD). Values bold if P value is <0.025.

Abbreviations: SLC6A4, solute carrier family 6, member 4; HTR2A, 5-hydroxytryptamine 2A receptor; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; PY, pack years smoked.

Significant P values (<0.025) are in bold.

No statistically relationship was observed between smoking habits or the clinical variables and SLC6A4 (rs25531).

As expected, we observed a correlation between PY as continuous variable and FEV1/FVC, FEV1% and FVC% (P=0.006, P=0.012 and P=0.014, respectively).

Discussion

In our study we found a statistically significant relationship between the allele A of HTR2A-1438G/A and COPD incidence. Moreover, we observed an association between this allele and PY or FEV1/FVC, however after stratification; we only replicate the results in the COPD group. These results could indicate that HTR2A variant affects COPD pathogenesis and this effect depends partly on tobacco consumption. The acute effects of cigarette smoking produce central nervous system–mediated activation of the sympathetic nervous system. The overactive sympathetic nervous system stimulates the secretion of serotonin (5-HT) and catecholamine into blood at supraphysiological levels.24 Serotonin receptors variants in COPD patients could overactivate a cascade of inflammatory reactions induced by smoking. Although preliminary, the results of our study provide evidence that genetic variations in HTR2A may influence both smoking habits and the development of COPD.

An association between HTR2A (rs6311) and smoking behavior has been reported.14,25 In addition, some authors have indicated an association of HTR2A (rs6311) with PH.3 However, this is the first report on an association between HTR2A (rs6311) variant and COPD.

HTR2A gene is located on chromosome 13q14-q21 and encodes a key membrane receptors of 5-HT. 5-HT, a biogenic amine, is one of the principal neurotransmitters in the central nervous system, interacts with a wide range of psychoactive compounds, including nicotine, and also acts as an important endocrine regulator, playing a key role in the functioning of the cardiovascular and the respiratory system.26

The activation of 5-HT receptors activates intracellular cascades that affect the functioning of other related systems (glutamatergic, dopaminegic, and GABA-ergic).27 Functional studies showed that the activation of 5-HT receptors regulates the release of interleukin-6 and interleukin-8.11 It was also found that 5-HT stimulates different signaling pathways and regulates cytokine release in epithelial cells of the respiratory pathways; thus, it is involved in the pathogenesis of bronchial asthma.11

On the other hand, The HTR2A gene has been regarded as one of the potential candidates for susceptibility to smoking. However, it is not a major contributing factor. The mesolimbic dopaminergic system mediates nicotine reinforcement in the brain, and this system is modulated by the serotonergic system via HTR2A.28 Experimental models have shown that cigarette smoke inhibits monoamine oxidase (MAO) leading to higher levels of 5-HT. Elevated levels of 5-HT are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence.5,6

The A allele of rs6311 increases promotor activity, mRNA expression and protein levels and increases receptor binding.29,30 This promoter polymorphism supports an hyperactive serotonergic system.31 In addition, Falkerlber et al. suggested that the promoter polymorphism (rs6311) can affect both transcription factor binding and promoter methylation, and this along with an individual's stress response can impact the rate of HTR2A transcription in a genotype and methylation-dependent manner.32 The rs6311 polymorphism of HTR2A was previously shown to be associated with nicotine dependence and smoking behavior.14,25 However, there is only one published study about rs6311 polymorphism of HTR2A and COPD risk and its results are not conclusive.16

Way et al. demonstrated the association between plasma 5-HT levels, and COPD. Higher plasma 5-HT levels were found in stable COPD patients compared to the control subjects. An up-regulation of serotonergic pathway due to HTR2A genotype and smoking could be related to higher inflammatory response of airway epithelial cells and higher risk of COPD.

On the other hand, there were no differences between SCL4A6 (rs25531) genotype and COPD. There are no previous studies that analyzed SLC4A6 (rs25531) polymorphism and COPD risk. An association between SCL4A6 (rs2020936) variant and smoking behavior or nicotine dependence has been reported.15,33 In addition, Ishii and cols. concluded that SCL4A6 (rs2020936) variant affects COPD pathogenesis and depressive symptoms in Japanese population.10 It should be noted that in this study, controls were a mixture of current and ex-smokers. Other authors have reported that SLC4A6 (rs25531) long allelic variant was associated with PH in COPD.3 Ulrich et al. supported a pathogenic role of the 5-HT system in the development of PH in COPD and the need for further studies in this field.3

The present study has several limitations. First, a limitation of the current study is its relatively small sample size, and as such, the findings require replication. To strengthen confidence in our findings we have selected an ethnically homogenous sample of Caucasians. Second, we have analyzed only two genetic variants of serotonin system genes. Other different variants in the 5-HT signaling pathway, such as described in tryptophan hydroxylase 2 (TPH2) and MAO type A, could be related to the pathogenesis.34

On the other hand, despite of the small simple size of the current study, our population is homogeneous, not stratified and well defined in terms of phenotype assessment and to our knowledge, this is the first study to evaluate the relationship between smoking intensity, COPD and the polymorphism HTR2A (rs6311) in Spanish population. Moreover the study follows the STREGA guidelines, all participants were randomly recruited in Hospital Gregorio Marañón Neumology Service by a pulmonary medicine specialist, genetic polymorphisms were selected attending their prevalence and functional impact in the protein, no departure from Hardy-Weinberg equilibrium was detected for the genetic polymorphisms or multiple testing and reporting of quantitative (continuous) outcomes were used). Better reporting of studies facilitate the synthesis of available research results and the further development of study methods in genetic epidemiology improving the understanding of the role of genetic factors in the cause of diseases.

Conclusions

Previous studies consider the hypothesis that, in addition to their involvement in nicotine dependence, 5-HT response in COPD patients could activate a cascade of inflammatory reactions induced by tobacco consumption. We speculate that the cigarette smoke-mediated injury in COPD lungs is partially mediated by HTR2A (rs6311). Despite the evidence that confer SCL4A6 gene and 5-HT response we have not found any relationship between SCL4A6 (rs25531) and COPD susceptibility.

In summary, although the effects of HTR2A (rs6311) alone are modest, our results suggest a possible role of the A allele of rs6311 in COPD pathogenesis, providing evidence that genetic variations in HTR2A may influence both, smoking habits and the development of COPD. Further investigation of the functional role and the regulation of 5-HT due to genetic variants in COPD is important for understanding and preventing the progression of this disease.

Funding

This study was supported by a grant of SEPAR (2006).

Conflict of interest

The authors declare no conflict of interest.

References
[1]
A.J. Alberg, D.R. Shopland, K.M. Cummings.
The 2014 Surgeon General's Report: Commemorating the 50th Anniversary of the 1964 Report of the Advisory Committee to the US Surgeon General and Updating the Evidence on the Health Consequences of Cigarette Smoking.
Am J Epidemiol, 179 (2014), pp. 403-412
[2]
M. Quaak, C.P. Van Schayck, A.M. Knaapen, F.J. Van Schooten.
Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?.
Eur Respir J, 33 (2009), pp. 468-480
[3]
S. Ulrich, M. Hersberger, M. Fischler, et al.
Genetic polymorphisms of the serotonin transporter, but not the 2a receptor or nitric oxide synthetase, are associated with pulmonary hypertension in chronic obstructive pulmonary disease.
Respiration, 79 (2010), pp. 288-295
[4]
S. Eddahibi, A. Chaouat, N. Morrell, et al.
Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease.
Circulation, 108 (2003), pp. 1839-1844
[5]
W.K.W. Lau, M.M.W. Chan-Yeung, B.H.K. Yip, A.H.K. Cheung, M.S.M. Ip, J.C.W. Mak.
The role of circulating serotonin in the development of chronic obstructive pulmonary disease.
[6]
I. Morecroft.
Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries.
J Pharmacol Exp Ther, 313 (2004), pp. 539-548
[7]
J.A. Barbera, V.I. Peinado, S. Santos.
Pulmonary hypertension in chronic obstructive pulmonary disease.
Eur Respir J, 21 (2003), pp. 892-905
[8]
P.J. Barnes, B.R. Celli.
Systemic manifestations and comorbidities of COPD.
Eur Respir J, 33 (2009), pp. 1165-1185
[9]
W. Xu, J. Collet, S. Shapiro, et al.
Independent effect of depression and anxiety on chronic obstructive pulmonary disease exacerbations and hospitalizations.
Am J Respir Crit Care Med, 178 (2008), pp. 913-920
[10]
T. Ishii, R. Wakabayashi, H. Kurosaki, A. Gemma, K. Kida.
Association of serotonin transporter gene variation with smoking, chronic obstructive pulmonary disease, and its depressive symptoms.
J Hum Genet, 56 (2011), pp. 41-46
[11]
H. Bayer, T. Müller, D. Myrtek, et al.
Serotoninergic receptors on human airway epithelial cells.
Am J Respir Cell Mol Biol, 36 (2007), pp. 85-93
[12]
D. Liolitsa, J.F. Powell, M. Prince, S. Lovestone.
Association study of the 5-HT(2A) receptor gene polymorphism, T102C and essential hypertension.
J Hum Hypertens, 15 (2001), pp. 335-339
[13]
S. Yamada, H. Akita, K. Kanazawa, et al.
T102C polymorphism of the serotonin (5-HT) 2A receptor gene in patients with non-fatal acute myocardial infarction.
Atherosclerosis, 150 (2000), pp. 143-148
S0021915099003561 [pii]
[14]
G. Pérez-Rubio, A. Ramírez-Venegas, V.N. Díaz, et al.
Polymorphisms in HTR2A and DRD4 predispose to smoking and smoking quantity.
[15]
Z. Verde, C. Santiago, J.M.R. González-Moro, et al.
“Smoking Genes”: a genetic association study.
[16]
G.F. Korytina, L.Z. Akhmadishina, O.V. Kochetova, Y.G. Aznabaeva, S.Z. Zagidullin, T.V. Victorova.
Polymorphic variants of glutamate receptor (GRIK5, GRIN2B) and serotonin receptor (HTR2A) genes are associated with chronic obstructive pulmonary disease.
Mol Biol (Mosk), 51 (2017), pp. 603-614
[17]
World Health Organization.
WHO global report on trends in prevalence of tobacco smoking 2015.
WHO Mag, (2015), pp. 1-359
doi:978 92 4 156492 2
[18]
J.I. Jaén Díaz, C. de Castro Mesa, M.J. Gontán García-Salamanca, F. López de Castro.
Prevalence of chronic obstructive pulmonary disease and risk factors in smokers and ex-smokers.
Arch Bronconeumol, 39 (2003), pp. 554-558
[19]
J. Ancochea, C. Badiola, E. Duran-Tauleria, et al.
Estudio EPI-SCAN: resumen del protocolo de un estudio para estimar la prevalencia de EPOC en personas de 40 a 80 años en España.
Arch Bronconeumol, 45 (2009), pp. 41-47
[20]
J. Little, J.P.T. Higgins, J.P.A. Ioannidis, et al.
STrengthening the REporting of genetic association studies (STREGA) – an extension of the STROBE statement.
Genet Epidemiol, 33 (2009), pp. 581-598
[21]
B.R. Celli, W. MacNee, A. Agusti, et al.
Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
Eur Respir J, 23 (2004), pp. 932-946
[22]
F. García-Río, M. Calle, F. Burgos, et al.
Spirometry. Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).
Arch Bronconeumol, 49 (2013), pp. 388-401
[23]
S.J. Chanock, T. Manolio, M. Boehnke, et al.
Replicating genotype-phenotype associations.
Nature, 447 (2007), pp. 655-660
[24]
D.F. Peterson, J.H. Coote, M.P. Gilbey, H.A. Futuro-Neto.
Differential pattern of sympathetic outflow during upper airway stimulation with smoke.
[25]
Z. Verde, C. Santiago, J. Rodríguez González-Moro, et al.
Are serotonergic system genes associated to smoking cessation therapy success in addition to CYP2A6?.
Pharmacopsychiatry, 47 (2014), pp. 33-36
[26]
P. Gong, J. Liu, P.R. Blue, S. Li, X. Zhou.
Serotonin receptor gene (HTR2A) T102C polymorphism modulates individuals’ perspective taking ability and autistic-like traits.
Front Hum Neurosci, 9 (2015),
[27]
J. Yang, M.D. Li.
Association and interaction analyses of 5-HT3 receptor and serotonin transporter genes with alcohol, cocaine, and nicotine dependence using the SAGE data.
Hum Genet, 133 (2014), pp. 905-918
[28]
M.J. Millan, F. Lejeune, A. Gobert.
Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents.
J Psychopharmacol, 14 (2000), pp. 114-138
[29]
O.O. Polesskaya, B.P. Sokolov.
Differential expression of the “C” and “T” alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics.
J Neurosci Res, 67 (2002), pp. 812-822
[pii]
[30]
G. Turecki, R. Brière, K. Dewar, et al.
Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide.
Am J Psychiatry, 156 (1999), pp. 1456-1458
[31]
A.J. Cleare, C. Messa, E.A. Rabiner, P.M. Grasby.
Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635.
[32]
V.R. Falkenberg, B.M. Gurbaxani, E.R. Unger, M.S. Rajeevan.
Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association.
NeuroMol Med, 13 (2011), pp. 66-76
[33]
S.L. Chu, X. Dan, W. Chen, J. Hang.
Association between 5-hydroxytryptamine transporter gene-linked polymorphic region and smoking behavior in Chinese males.
Chin Med J (Engl), 122 (2009), pp. 1365-1368
[34]
J.E. Lim, J. Pinsonneault, W. Sadee, D. Saffen.
Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons.
Mol Psychiatry, 12 (2007), pp. 491-501
Copyright © 2018. SEPAR
Archivos de Bronconeumología
Article options
Tools

Are you a health professional able to prescribe or dispense drugs?