Scientific Letter
Identification of Genetic Factors Associated With DAMP Release in COPD Patients
Fia Sabrina Boedijonoa,b, Verena Boodc,d,e, Ilse A. Eichhornc,d,e, Philip M. Hansbrob, Dirk-Jan Slebosc,e, Maarten van den Bergec,e, Alen Faiza,1, Simon D. Pouwelsc,d,e,1,
Corresponding author
a Respiratory Bioinformatics and Molecular Biology Group, University of Technology Sydney, Australia
b Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, Australia
c Department of Pulmonary Diseases, University Medical Center Groningen, The Netherlands
d Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands
e GRIAC Research Institute, University of Groningen, Groningen, The Netherlands
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"apellidos" => "Pouwels" "email" => array:1 [ 0 => "s.d.pouwels@umcg.nl" ] "referencia" => array:5 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] 4 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Respiratory Bioinformatics and Molecular Biology Group, University of Technology Sydney, Australia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, Australia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Pulmonary Diseases, University Medical Center Groningen, The Netherlands" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "GRIAC Research Institute, University of Groningen, Groningen, The Netherlands" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2180 "Ancho" => 2100 "Tamanyo" => 359510 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Association between serum DAMP levels and the number of rare variants within a gene. A genome-wide burden test was performed to test the association between the serum levels of (A) dsDNA, (B) Galectin-9, (C) sRAGE, and (D) α-Defensin and the number of variants within a specific gene. The genomic location, and corresponding chromosomes are shown on the <span class="elsevierStyleItalic">x</span>-axis and the log transformed <span class="elsevierStyleItalic">p</span>-values are shown on the <span class="elsevierStyleItalic">y</span>-axis, a corrected <span class="elsevierStyleItalic">p</span>-value higher than −log<span class="elsevierStyleInf">10</span>(<span class="elsevierStyleItalic">p</span>) was considered statistically significant (presented as a horizontal line). (E) Association between the serum levels of Galectin-9 and broncho-epithelial gene expression of KIF18A. Pearson correlation coefficient (<span class="elsevierStyleItalic">r</span>) and associated <span class="elsevierStyleItalic">p</span>-value are shown.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Over the past decade it has become increasingly evident that endogenous danger signals, called damage associated molecular patterns (DAMPs), released from damaged or dying lung resident cells play a pivotal role in the pathophysiology of chronic obstructive pulmonary disease (COPD).<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1,2</span></a> It has been consistently shown that the levels of DAMPs are increased in the lungs of COPD patients compared to non-COPD controls, in bronchoalveolar lavage fluid, epithelial lining fluid or sputum,<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">3–5</span></a> as well as systemically in serum or plasma.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">6–8</span></a> These increased DAMP levels originate from structural and immune cells that are exposed to damaging agents upon inhalation of toxic gases and particles, like cigarette smoke, exhaust fumes or air pollution.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">9,10</span></a> Previously, we showed that the amount and type of DAMPs that are released upon inhalation of cigarette smoke, has a strong genetic component.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">11–13</span></a> However, to date it is still unknown which genetic factors increase the susceptibility for DAMP release. This study aimed to increase our understanding of the factors involved in susceptibility to DAMP release, which are potentially contributing to the susceptibility to develop COPD. This is the first study assessing the association between genetic factors and the levels of DAMPs in serum.</p><p id="par0010" class="elsevierStylePara elsevierViewall">To this end, data was collected from 165 severe COPD (GOLD stage 3–4) patients of the Groningen Severe COPD cohort (<a href="ctgov:NCT04023409">NCT04023409</a>), who were all ex-smokers with >5 pack-years of smoking history but have not smoked for >6 months prior to sampling. Forty-nine of the subjects were male with a mean age of 55 years (between 36 and 77), an average number of pack-years of 36.7 (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15.0), average lung function of 28 (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6.7; FEV1/FVC%), and a mean emphysema score of 40.2% (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7.5; %voxels <950 Hounsfield Units upon expiration). The study was approved by the medical ethical committee of the University Medical Center Groningen, and all participants provided written informed consent.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A panel of 4 DAMPs (α-Defensin, Galectin-9, sRAGE, dsDNA) was measured in serum of 165 COPD patients. The levels of α-Defensin (Human alpha-Defensin 1 DuoSet ELISA, DY8198-05, R&D Systems, Minneapolis, MN), Galectin-9 (Human Galectin-9 DuoSet ELISA, DY2045, R&D Systems) and the soluble Receptor for Advanced Glycation End-products (sRAGE; Human RAGE DuoSet ELISA, DY1145, R&D Systems) were measured by ELISA according to the manufacturer's protocols. The levels of double-stranded (ds)DNA were measured using Quant-iT™ PicoGreen™ dsDNA Assay Kits (P7589, Invitrogen, Waltham, MS). Whole-exome sequencing was performed on blood DNA using the Illumina platform and subsequently mapping the sequence to the Human Genome build 38. Full-genome gene expression data was obtained from bronchial brushes from 123 of the donors. The number of rare variants within a gene was assessed with the burden test using the sequence kernel association test (SKAT) method.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleItalic">p</span>-Values were computed using the SKAT_Null_Model function, in which each DAMP was defined as a continuous trait, and correction for age and smoking history was applied. Multiple testing correction was performed using the Bonferroni correction.</p><p id="par0020" class="elsevierStylePara elsevierViewall">To test whether the levels of DAMPs in serum associated with the amount of potentially damaging rare variants of a gene, a genome-wide burden test was performed. This test assessed the associations between all variants within a gene and the serum levels of DAMPs. Manhattan plots indicate the different genes and their genomic location that were found to be significantly associated with the levels of dsDNA, Galectin-9, sRAGE and α-Defensin in serum (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A–D). Nine genes were identified containing significantly more rare variants in COPD patients with high serum levels of dsDNA (<span class="elsevierStyleItalic">HHLA2</span>, <span class="elsevierStyleItalic">ORM1</span>, <span class="elsevierStyleItalic">MROH6</span>, <span class="elsevierStyleItalic">SYT7</span>, <span class="elsevierStyleItalic">GJB4</span>, <span class="elsevierStyleItalic">HEATR6</span>, <span class="elsevierStyleItalic">OR2V2</span>, <span class="elsevierStyleItalic">TF</span>, <span class="elsevierStyleItalic">PLEK2</span>). Eleven genes contained significantly more rare variants in COPD patients with high serum levels of Galectin-9 (<span class="elsevierStyleItalic">TRAPPC2L</span>, <span class="elsevierStyleItalic">LYZ</span>, <span class="elsevierStyleItalic">C8B</span>, <span class="elsevierStyleItalic">RGS9</span>, <span class="elsevierStyleItalic">SOAT2</span>, <span class="elsevierStyleItalic">ZBTB32</span>, <span class="elsevierStyleItalic">PDE11A</span>, <span class="elsevierStyleItalic">OR5H6</span>, <span class="elsevierStyleItalic">HAPLN3</span>, <span class="elsevierStyleItalic">IGLV5-45</span>, <span class="elsevierStyleItalic">ANKRD22</span>), while two genes contained more rare variants in COPD patients with high levels of sRAGE (<span class="elsevierStyleItalic">FAM175A</span>, <span class="elsevierStyleItalic">AARS2</span>). No genes were associated with the serum levels of α-Defensin. No obvious molecular pathways or biological functions were found to be related to the identified genes upon performing gene ontology enrichment analysis (The STRING database, <a href="http://string-db.org/">http://string-db.org</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Next, the associations between serum levels of DAMPs and single nucleotide polymorphisms (SNPs) were assessed, using a protein quantitative trail locus (pQTL) analysis. Rare variants with a minor allele frequency of <4% were excluded. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the five SNPs that were identified to be significantly associated with the serum levels of DAMPs. Two of the SNPs were in full linkage disequilibrium (LD). The SNPs were located within the coding region of four different genes. No overlap between the identified pQTLs and genes containing more rare variants was found.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Next, to test whether the identified SNPs affected the expression of the associated genes, broncho-epithelial gene expression of the four identified genes, <span class="elsevierStyleItalic">i.e.</span><span class="elsevierStyleItalic">SLC4A4</span>, <span class="elsevierStyleItalic">VAV1</span>, <span class="elsevierStyleItalic">KIF18A</span> and <span class="elsevierStyleItalic">SEMA6C</span>, were correlated with the levels of the associated DAMPs in serum. No correlation was found between serum dsDNA levels and <span class="elsevierStyleItalic">SLC4A4</span> and <span class="elsevierStyleItalic">VAV1</span> or between serum sRAGE and <span class="elsevierStyleItalic">SEMA6C</span>. However, a small but borderline significant correlation was found between the serum levels of Galectin-9 and bronchial gene expression of <span class="elsevierStyleItalic">KIF18A</span> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>E).</p><p id="par0035" class="elsevierStylePara elsevierViewall">This is the first study investigating the genetic factors involved in susceptibility to DAMP release. We identified five SNPs, located within the coding region of four genes that are associated with the levels of DAMPs in serum of COPD patients. Out of these SNPs, only rs12272419 within the <span class="elsevierStyleItalic">KIF18A</span> gene is a missense variant leading to an amino acid change, potentially explaining why only the bronchial gene expression of <span class="elsevierStyleItalic">KIF18A</span> correlated with serum DAMP levels. KIF18A, a member of the kinesin superfamily, is involved in cell proliferation and mitosis, by regulating the dynamics of microtubule-associated molecular motors. Over-expression of KIF18A promotes cell proliferation and inhibits apoptosis.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">15</span></a> It is possible that in COPD, a disease where cell death processes like apoptosis, necroptosis and efferocytosis are dysregulated,<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">16,17</span></a> further dysregulation of the cell death and proliferation mechanisms contribute to additional DAMP release. Likewise, sodium bicarbonate cotransporter 1 (SLC4A4), is also involved in the regulation of cell death, as it is involved in necroptosis, a regulated form of necrosis.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> Necroptosis has been shown to be one of the main contributors of DAMP release upon inhalation of cigarette smoke,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> and is increased in experimental and human COPD models.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The amount of rare variants of specific genes was found to be associated with the levels of DAMPs in serum of COPD patients. No specific pathway or relationship between the identified genes was observed. Future studies should be focused on identifying the exact role of the increased number of rare variants within these genes and the levels of DAMPs in serum. It is likely that the increased number of mutations of these genes contribute to the release of DAMPs in the lungs upon cell damage, yet it is also possible that high levels of DAMPs in serum increases the mutation frequency of specific genes. The panel of DAMPs was selected to comprise a range of DAMPs originating from different subcellular compartments and that can activate different pattern recognition receptors. However, it is possible that a different selection of DAMPs would have led to the identification of different DAMPs.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Although we aimed to identify general susceptibility genes for DAMP release, we chose to use a cohort consisting exclusively out of COPD patients, since these patients have higher systemic levels of DAMPs. To this end, we cannot exclude the possibility that the identified susceptibility genes are related to DAMP release only in COPD patients. Future studies should be aimed at validating whether the DAMP release-related genes identified in this study are also involved in DAMP release in non-COPD patients.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In conclusion, this study confirmed that the susceptibility to the release of DAMPs has a strong genetic component. Several SNPs and susceptibility genes were identified that are associated with the release of DAMPs in COPD patients.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical Approval</span><p id="par0055" class="elsevierStylePara elsevierViewall">The study was approved by the medical ethical committee of the University Medical Center Groningen, and all subjects provided written informed consent. Severe COPD patients are derived from ClinicalTrials.gov Identifier: <a href="ctgov:NCT04023409">NCT04023409</a>. Data from these study cohorts can be accessed through collaboration by contacting Maarten van den Berge (<a href="mailto:m.van.den.berge@umcg.nl">m.van.den.berge@umcg.nl</a>).</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0060" class="elsevierStylePara elsevierViewall">Simon D. Pouwels was funded by a Dutch Research Council (NWO) VENI grant (no. 09150162010003).</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Authors’ Contributions</span><p id="par0065" class="elsevierStylePara elsevierViewall">Concept & design: AF, SDP. Data analysis: FSB, AF, SDP. Patient inclusion/data collection: VB, IAE, MvdB, DJS, PMH. Project supervision: SDP. Manuscript preparation: SDP. Manuscript revision: FSB, VB, IAE, PMH, DJS, MvdB, AF, SDP.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conflict of Interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">None declared.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Declaration of Artificial Intelligence Involvement</span><p id="par0075" class="elsevierStylePara elsevierViewall">No artificial intelligence was used for this study, nor for the writing of the manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical Approval" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Authors’ Contributions" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of Interest" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Declaration of Artificial Intelligence Involvement" ] 5 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">These authors contributed equally.</p>" "identificador" => "fn0005" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2180 "Ancho" => 2100 "Tamanyo" => 359510 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Association between serum DAMP levels and the number of rare variants within a gene. A genome-wide burden test was performed to test the association between the serum levels of (A) dsDNA, (B) Galectin-9, (C) sRAGE, and (D) α-Defensin and the number of variants within a specific gene. The genomic location, and corresponding chromosomes are shown on the <span class="elsevierStyleItalic">x</span>-axis and the log transformed <span class="elsevierStyleItalic">p</span>-values are shown on the <span class="elsevierStyleItalic">y</span>-axis, a corrected <span class="elsevierStyleItalic">p</span>-value higher than −log<span class="elsevierStyleInf">10</span>(<span class="elsevierStyleItalic">p</span>) was considered statistically significant (presented as a horizontal line). (E) Association between the serum levels of Galectin-9 and broncho-epithelial gene expression of KIF18A. Pearson correlation coefficient (<span class="elsevierStyleItalic">r</span>) and associated <span class="elsevierStyleItalic">p</span>-value are shown.</p>" ] ] 1 => 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="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">p</span>-Values represent the nominal <span class="elsevierStyleItalic">p</span>-value. A genome-wide false discovery rate (FDR) of <0.05 was considered genome-wide significant. Rs149865022 and rs76873911 are in full linkage disequilibrium.</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SNP \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DAMP \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Beta \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-Value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FDR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MAF % \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variant Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene Name \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs1453458 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dsDNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−100.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.93E−08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.054 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Synonymous variant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SLC4A4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Solute carrier family 4 member 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs149865022/rs76873911 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dsDNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.24E−06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0215 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.042 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intron variant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VAV1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vav guanine nucleotide exchange factor 1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs12272419 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gal-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1156.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.78E−08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0051 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.042 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Missense variant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">KIF18A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kinesin family member 18A \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs74949844 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">sRAGE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">321.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.80E−07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0146 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.061 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Synonymous variant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SEMA6C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Semaphorin 6C \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3715769.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Significant Associations Between the Serum Levels of DAMPs and SNPs.</p>" ] ] 2 => array:6 [ "identificador" => "202411050535071801" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 196 "Ancho" => 192 "Tamanyo" => 6243 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "sat0005" "detalle" => "Twitter Ico" "rol" => "short" ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0100" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of epithelial damage in the pulmonary immune response" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.A. 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