Outcomes trials
A genome-wide association study identifies protective CETP gene variants underlying cardiovascular resilience in older adults (J Am Heart Assoc 2023)
Original title: Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene
To find cardioprotective variants explaining why some high-risk older individuals remain free of atherosclerotic cardiovascular disease, researchers performed a genome-wide association study of 10-year predicted ASCVD risk as a quantitative trait in 12 031 event-free ASPREE trial participants aged 70 or older, discovering two independent CETP gene variants, rs9939224 and rs56156922. These associations were replicated in 13 888 similarly aged, event-free UK Biobank participants. Carriers of the identified CETP variants had higher HDL cholesterol, lower LDL cholesterol, and reduced risk of incident ASCVD events during follow-up, with expression quantitative trait locus analysis predicting the variants reduce CETP gene expression across tissues; reassuringly, the previously reported association between genetic CETP inhibition and age-related macular degeneration risk was not observed among the 3917 ASPREE participants with retinal imaging and genetic data available.
Original abstract
Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P<5×10-8) and rs56156922 (P<10-6), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high-density lipoprotein cholesterol levels, lower plasma low-density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow-up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age-related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
the classgeneticsoutcomes trials
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.