0026 Targeted genome sequencing identifies multiple rare variants in Caveolin-1 associated with obstructive sleep apnea

Abstract

Abstract Introduction Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes. Methods Leveraging high depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleveland Family Study followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 European-Americans. Results We identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (P = 7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence. Follow-up analysis revealed significant associations between increased CAV1 expression with lower AHI (P=0.024) and higher minimum overnight oxygen saturation (P=0.007). Conclusion Caveolin-1 is a membrane scaffolding protein that is essential in the formation of plasma membrane lipid rafts and mediates cholesterol trafficking; regulates several signaling molecules including transforming growth factor β (TGF-beta), Toll Like Receptor 4 (TLR4) and endothelial nitric oxide synthase (eNOS); with mutations implicated in disorders associated with OSA: pulmonary hypertension, diabetes, atherosclerosis, endothelial and cardiac dysfunction, and inflammation. Our results indicate that caveolin-1 also plays a significant role in OSA, with rare variants and higher CAV1 expression associated with lower AHI. Support (If Any) R35HL135818, R01HG011052, R01HL153814