Associations of Sleep Apnea, NRG1 Polymorphisms, Alcohol Consumption, and Cerebral White Matter Hyperintensities: Analysis with Genome-Wide Association Data

Abstract

Study Objective: There are few studies on gene-environment interactions with obstructive sleep apnea (OSA). Our study aimed to explore genetic polymorphisms associated with OSA using genome-wide association (GWA) data and evaluate the effects of relevant polymorphisms on the association between risk factors, including obesity and alcohol consumption, and OSA. We also investigated on these associations in relation to cerebral white matter hyperintensities (WMH) on magnetic resonance images. Design: A cross-sectional design. Setting: A polysomnography study embedded in a population-based cohort from the Korean Genome Epidemiology Study was conducted in 2011-2013. Participants: 1,763 participants aged 48-78 years. Results: 251 individuals were identified to have OSA with an apnea-hypopnea index >= 15. A common polymorphism of neuregulin-1 gene (NRG1), rs10097555, was selected as the most suggestive locus associated with OSA (P value < 10(-5)) based on the results of GWA analysis in a matched case-control subsample (n = 470). Among 1,763 participants, we found that the presence of the NRG1 polymorphism is inversely associated with OSA (P value < 0.01) even after taking into account potential risk factors; the multivariate odds ratio (95% confidence interval) for the mutant alleles was 0.57 (0.39-0.82) compared with the wild-type. We observed that this association is modified by alcohol consumption (P < 0.05), not by obesity. We also observed that WMH are positively associated with OSA independent of the NRG1 polymorphism and alcohol consumption (P < 0.05). Conclusions: These findings suggest that the neuregulin-1 gene (NRG1) may be involved in the etiological mechanisms of obstructive sleep apnea (OSA) and that carriers of a particular NRG1 mutation may be less likely to have OSA if they do not drink alcoholic beverages.