Genotype–phenotype interactions in pediatric obstructive sleep apnea

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Abstract

Pediatric sleep disordered breathing (PSDB) is not only a very frequent condition affecting 2–4% of all children, but is also associated with an increased risk for a variety of manifestations underlying end-organ injury and dysfunction that impose both immediate and potentially long-term morbidities and corresponding inherent elevations in healthcare costs. One of the major problems with the creation of valid algorithms aiming to stratify diagnostic and treatment prioritization lies in our current inability to predict and identify those children who are most at-risk for PSDB-induced adverse consequences. Thus, improved our understanding of the mechanisms governing phenotype variance in PSDB is essential. Here, we examine some of the potential underpinnings of phenotypic variability in PSDB, and further propose a conceptual framework aimed at facilitating the process of advancing knowledge in this frequent disorder.

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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