TY - JOUR
T1 - Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene
AU - Yu, Chenglong
AU - Bakshi, Andrew
AU - Watts, Gerald F.
AU - Renton, Alan E.
AU - Fulton-Howard, Brian
AU - Goate, Alison M.
AU - Natarajan, Pradeep
AU - Chasman, Daniel I.
AU - Robman, Liubov
AU - Woods, Robyn L.
AU - Guymer, Robyn
AU - Wolfe, Rory
AU - Thao, Le Thi Phuong
AU - McNeil, John J.
AU - Tonkin, Andrew M.
AU - Nicholls, Stephen J.
AU - Lacaze, Paul
N1 - Funding Information:
The ASPREE (ASPirin in Reducing Events in the Elderly) trial Biobank is supported by a Flagship cluster grant (including the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne); and a grant (5U01AG29824-02) from the National Cancer Institute at the National Institutes of Health; and Monash University. The ASPREE project is supported by grants (U01AG029824 and U19AG062682) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health; and by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia; and by Monash University and the Victorian Cancer Agency. Paul Lacaze is supported by a National Heart Foundation Future Leader Fellowship (102604). John J. McNeil is supported by a Leadership Fellowship from National Health and Medical Research Council of Australia (IG1173690). Robyn Guymer is supported by investigator grant 1194667 from National Health and Medical Research Council of Australia. Pradeep Natarajan is supported by grants from the National Heart, Lung, and Blood Institute at the National Institutes of Health (R01HL142711 and R01HL127564). Alan E. Renton, Brian Fulton-Howard, and Alison M. Goate are supported by a grant (U01AG058635) at the National Institutes of Health. The ASPREE-AMD (Age-Related Macular Degeneration) sub-study was supported by the National Health and Medical Research Council of Australia (grant 1051625), National Eye Institute at the National Institutes of Health (grant R01EY026890), Monash University and Centre for Eye Research Australia.
Publisher Copyright:
© 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2023/11/7
Y1 - 2023/11/7
N2 - 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.
AB - 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.
KW - aging
KW - cardioprotective variants
KW - cardiovascular disease
KW - genome-wide association study
KW - lipid metabolism
UR - http://www.scopus.com/inward/record.url?scp=85176310553&partnerID=8YFLogxK
U2 - 10.1161/JAHA.123.031459
DO - 10.1161/JAHA.123.031459
M3 - Article
C2 - 37929782
AN - SCOPUS:85176310553
SN - 2047-9980
VL - 12
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 21
M1 - e031459
ER -
