Genotype–phenotype interactions in pediatric obstructive sleep apnea☆
Section snippets
Pediatric sleep disordered breathing (PSDB)
Obstructive sleep apnea syndrome (OSA) is a common condition in children affecting up to 2–4% of all children with a peak incidence between 1 and 8 years of age (Kaditis, 2012).
Increased upper airway resistance or periodic obstructions of the upper airway during sleep lead to increased intrathoracic inspiratory pressures, intermittent oxyhemoglobin desaturations that are usually accompanied by PaCO2 elevations, and promote the disruption of sleep integrity as manifested by EEG arousals,
Pathophysiological mechanisms in PSDB
It is now clear that no single causative factor can be ascribed as solely responsible for the occurrence of OSA. However, the interplay between 4 major factors may in fact account for the vast majority, if not for the totality of the cases in otherwise healthy children. More specifically, interactions between craniofacial and anatomical factors, lymphoid tissue growth patterns, upper airway inflammation, and neuromuscular reflexes appear to underlie the emergence of OSA. Taken together, these
Morbid consequences of OSA
It should not be surprising to anyone that the major impetus driving the investigation of any given condition is the fact that such condition promotes the occurrence of adverse complications. In the last 3 decades, an ever growing number of studies have revealed significant associations between PSDB and multiple end-organ morbidities, primarily affecting CNS, cardiovascular, and metabolic systems (Gozal and Kheirandish-Gozal, 2012). A cardinal observation pertaining to any of these associations
Genetic determinants of morbidity in PSDB
It is rather unfortunate that the field of genetic exploration of PSDB is really in its infancy. Indeed, only a limited number of reports on the associations between specific gene polymorphisms and PSDB-associated morbidity is currently available, but such preliminary findings further buttress the validity and the need for large population-based genome-wide association studies (GWAS) in this area.
PSDB morbidity and the epigenome
The compelling evidence presented thus far to illustrate the large variance in phenotypic expression of PSDB raises the possibility that among the genetic factors that underlie such variance, epigenetic modifications could be present among genes involved in inflammatory, vascular, neurocognitive or metabolic functions. Such changes in the epigenome would alter gene transcriptional activity, be potentially transmissible to subsequent generations, in the absence of any changes within the primary
Conclusions
The existence of phenotype-genotype interactions in the context of PSDB appears to be irrefutable at this stage, in spite of the scarce cumulative evidence collected thus far in this context. It is highly likely that more in-depth characterization of such interactions will enable the formulation of a risk prediction signature panel for each of the morbidities associated with pediatric OSA. Identification of “vulnerable patients” based on the presence of specific gene variants, either in
Funding sources
DG is supported by National Institutes of Health grants HL-65270, HL-086662, and HL-107160.
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Future directions
2023, Snoring and Obstructive Sleep Apnea in ChildrenPolysomnographic Characteristics of Snoring Children: A Familial Study of Obstructive Sleep Apnea Syndrome
2021, Archivos de BronconeumologiaCitation Excerpt :The prevalence and clinical relevance of OSA among children has increased over the past decade.6 Although adenotonsillar hypertrophy is the major contributor to the pathophysiology of OSA in the pediatric age, environmental and genetic factors potentially interact in the pathogenesis of pediatric OSA.7–9 Nevertheless, there are limited data regarding the identification of risk factors which may assist in the assessment of susceptible pediatric population.10
Circulating exosomes in obstructive sleep apnea as phenotypic biomarkers and mechanistic messengers of end-organ morbidity
2018, Respiratory Physiology and NeurobiologyCitation Excerpt :Several oxidative stress markers are increased in OSAS, and could amplify inflammatory cascades, induce endothelial dysfunction and development of atherosclerosis and promote central nervous system dysfunction (Lavie, 2003, 2015; Wang et al., 2010; Zhang et al., 2012; Zhou et al., 2016). However the determinants of injury in any given patient with OSA are not well delineated, and in addition to disease severity and concurrent presence of other underlying conditions such as obesity, they are likely to involve both genetic and environmental contributions (Bhattacharjee et al., 2011; Kheirandish-Gozal and Gozal, 2013; Tan et al., 2014). Obesity has rapidly evolved into a global pandemic, and poses a significant healthcare and socioeconomic burden in both developed and developing countries.
Phenotypes of sleep-disordered breathing symptoms to two years of age based on age of onset and duration of symptoms
2018, Sleep MedicineCitation Excerpt :We present findings from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study where we sought to determine patterns of SDB symptoms (SDB phenotypes) based on age of onset and duration of symptoms. Childhood SDB may comprise multiple overlapping phenotypes depending on a child’s craniofacial anatomy, tonsil and adenoid growth, body habitus, and presence of rhinitis symptoms [10]. We hypothesized that the different symptom phenotypes may be distinguished by age of onset and duration of symptoms.
Morbidity of Pediatric Obstructive Sleep Apnea in Children: Myth, Reality, or Hidden Iceberg?
2018, Archivos de Bronconeumologia
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This paper is part of a special issue entitled “Clinical Challenges to Ventilatory Control”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracy Baker-Herman and Dr. David Paydarfar.