A polygenic risk score improves the prediction of cardiovascular risk associated with obstructive sleep-apnea

ABSTRACT Introduction Obstructive sleep apnea (OSA) carries increased cardiovascular (CV) risk. However, this risk is not fully captured by the apnea–hypopnea index (AHI). We investigated whether a validated coronary artery disease polygenic risk score (CAD-PRS) refines CV risk assessment in OSA. Methods We derived CAD-PRS using genome-wide genotyping data for 1,379 participants of the CoLaus|HypnoLaus cohort who underwent polysomnography. Associations between OSA, CAD-PRS, clinical factors, and incident CV events were assessed using multivariable Cox proportional hazards models. Risk stratification improvement was assessed with reclassification analyses compared to clinical risk scores (SCORE2/SCORE2-OP). Results During 7.2 years of median follow-up, 100 participants experienced CV events. A significant interaction between OSA and CAD-PRS was observed (p=0.013). The effect of OSA on CV risk differed across PRS categories. In the intermediate genetic-risk group (CAD-PRS quintiles 2–4), OSA patients (AHI ≥15/h) had a markedly higher CV risk compared to non-OSA (HR[95% CI]: 2.68[1.54–4.66]), whereas OSA did not significantly increase CV risk in either the low or high PRS strata. The complete model with OSA, CAD-PRS and their interaction allowed a significant reclassification (Net Reclassification Index 0.171, p=0.014) compared to SCORE2/SCORE2-OP and 52% of individuals at intermediate risk were reclassified as low or high CV risk. Conclusion A CAD-PRS refines CV risk stratification in individuals with OSA. The impact of OSA on CV risk is greatest in individuals with intermediate genetic risk. Adding CAD-PRS and OSA to SCORE2 improves model performance and reclassification, supporting more precise CV risk assessment in OSA. Statement of significance Obstructive sleep apnea is common, however the apnea–hypopnea index alone does not adequately capture associated cardiovascular risk. In this study, we evaluated whether a polygenic risk score for coronary artery disease can refine cardiovascular risk assessment in people with sleep apnea. Both sleep apnea and genetic risk were independently associated with incident cardiovascular events beyond standard clinical risk scores. Importantly, we found a significant interaction: excess cardiovascular risk related to moderate-to-severe sleep apnea was mainly confined to individuals with an intermediate genetic risk, while those at low or very high genetic risk were less affected. These findings support the potential value of incorporating genetic information to enable more nuanced and personalized cardiovascular risk assessment in sleep apnea.