Abstract 4364058: Polygenic Risk Scores Do Not Fully Explain Resilience to CVD in Individuals from Long Lived Families: UK Biobank

Background: Resilience to aging diseases is observed in families with a history of extreme longevity. They may be protected by 3 potential genetic mechanisms: 1) carrying a lower disease risk burden as reflected in polygenic risk scores (PRS), 2) carrying rare disease-resilience genetic variants that are not included in the PRS, or 3) carrying protective genotypes that buffer the effect of common genetic risk factors in PRS. We investigated genetic resilience to CVD by comparing specific PRS in the offspring of parents with extreme longevity (OPEL) to offspring of usual survival (OPUS) in the UK Biobank. Methods: OPEL (n=9,584) was defined as having at least one parent in the top percentile of survival; father ≥ 95 years, mother ≥ 97 years. OPUS (n=180,042) was defined as both parents with usual survival; father < 84 years and mother < 87 years. PRS of cardiovascular outcomes were available from the UK Biobank. We considered time to cardiovascular events of myocardial infarction, stroke, and Ischemic Stroke (ISS) from the time of enrollment. Cox proportional hazards models were used to assess the effect of PRS and family history on men and women separately, with deprivation index as a covariate. Results: OPUS on average had higher cardiovascular PRS than OPEL. The difference was moderate in size (0.20 to 0.24) but statistically significant. However, PRS did not fully explain the significantly lower cardiovascular disease risk among OPEL. The hazard ratio (HR) of OPUS over OPEL remained highly elevated after we adjusted for PRS in the model (Table). Furthermore, we found no evidence that the effect of PRS was reduced in OPEL. Conclusions: Exceptional parental longevity is associated with reduced risk of cardiovascular disease in offspring of long-lived parents, independent of known polygenic risk scores. PRS explained only a small fraction of the protective effect observed in OPEL individuals. These findings suggest that rare or undiscovered genetic variants may underlie familial longevity and disease resilience, offering potential targets for future research on healthy aging and disease prevention.