A polygenic risk score modifies the cardiovascular risk associated with obstructive sleep apnea

ABSTRACT Study Objectives 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 (HR95% CI: 2.681.54–4.66), 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. Conclusions In this population-based cohort, a CAD-PRS was associated with CV risk stratification in individuals with OSA. The impact of OSA on CV risk was greatest in individuals with intermediate genetic risk. Adding CAD-PRS and OSA to SCORE2 was associated with improved model performance and reclassification, supporting more precise CV risk assessment in OSA.