Pathway-specific genetic risk of CAD differs between individuals with and without obstructive sleep apnea, indicating a gene-by-environment interaction not captured by genome-wide risk scores.
Cross-Sectional (n=471,877)
Does pathway-specific genetic risk of CAD differ between individuals with and without obstructive sleep apnea?
Pathway-specific genetic risk scores reveal gene-by-environment interactions between obstructive sleep apnea and coronary artery disease risk that are not captured by standard genome-wide polygenic risk scores.
BACKGROUND: Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia, may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (eg, inflammatory) and protective (eg, increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. METHODS: We selected a cross-sectional sample of 471 877 participants from the UK Biobank, with 4974 ascertained to have OSA, 25 988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (Coronary ARtery DIsease Genome wide Replication and Meta-analysis CARDIoGRAM plus The Coronary Artery Disease C4D Genetics), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with intermittent hypoxia and CAD, we tested pathway-specific polygenic risk scores for the HIF1 (hypoxia-inducible factor 1), VEGF (vascular endothelial growth factor), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and TNF (tumor necrosis factor) signaling pathways. RESULTS: ). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA. CONCLUSIONS: We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. This invites further study of how OSA interacts with genetic risk at the molecular level and suggests eventual personalization of OSA treatment to reduce CAD risk according to individual pathway-specific genetic risk profiles.
Goodman et al. (2022) conducted a cross-sectional in Coronary artery disease and obstructive sleep apnea (n=471,877). Pathway-specific polygenic risk scores vs. Genome-wide polygenic risk scores was evaluated on Statistical interaction between pathway-specific polygenic risk scores and OSA for CAD risk. Pathway-specific genetic risk of CAD differs between individuals with and without obstructive sleep apnea, indicating a gene-by-environment interaction not captured by genome-wide risk scores.