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Multicenter Study
. 2024 Nov;17(11):e016377.
doi: 10.1161/CIRCIMAGING.123.016377. Epub 2024 Nov 13.

Polygenic Risk Scores and Extreme Coronary Artery Calcium Phenotypes (CAC=0 and CAC≥1000) in Adults ≥75 Years Old: The ARIC Study

Omar Dzaye  1 , Alexander C Razavi  1   2 , Zeina A Dardari  1 , Frances M Wang  3 , Yasuyuki Honda  3 , Khurram Nasir  4 , Josef Coresh  3 , Candace M Howard-Claudio  5 , Jin Jin  6 , Bing Yu  7 , Paul S de Vries  7 , Lynne Wagenknecht  8 , Aaron R Folsom  9 , Ron Blankstein  10 , Tanika N Kelly  11 , Seamus P Whelton  1 , Martin Bødtker Mortensen  1   12 , Ziqiao Wang  6 , Nilanjan Chatterjee  6 , Kunihiro Matsushita  3 , Michael J Blaha  1
Affiliations
Multicenter Study

Polygenic Risk Scores and Extreme Coronary Artery Calcium Phenotypes (CAC=0 and CAC≥1000) in Adults ≥75 Years Old: The ARIC Study

Omar Dzaye et al. Circ Cardiovasc Imaging. 2024 Nov.

Abstract

Background: Coronary artery calcium (CAC) is heterogeneous in older age and is incompletely explained by traditional atherosclerotic cardiovascular disease risk factors. The extremes of subclinical atherosclerosis burden are strongly associated with either a low or high 10-year risk of incident atherosclerotic cardiovascular disease, respectively. However, the genetic underpinnings of differences in arterial aging remain unclear. We sought to determine the independent association of 2 polygenic scores for coronary heart disease (CHD) with CAC in adults ≥75 years of age.

Methods: There were 1865 ARIC (Atherosclerosis Risk in Communities) participants who underwent genetic testing at visit 1 (1987-1989) and CAC scans at visit 7 (2018-2019). In the primary analysis, an externally derived multi-ancestry polygenic CHD risk score was calculated for both White and Black participants. Results were confirmed using a separate ARIC-derived polygenic CHD risk score, including ≥6 million variants computed for White participants. We used multivariable logistic regression models to assess the association of polygenic CHD risk with CAC, after adjusting for baseline, time-averaged lifestyle, traditional risk factors, and local ancestry principal components.

Results: In the primary analysis, the average age was 80.6 years old, 61.6% were women, and the median CAC score was 246 (189 participants with CAC=0, 364 participants with CAC≥1000). Compared with persons below the 20th percentile of polygenic CHD risk, persons with polygenic-CHD risk above the 80th percentile had 82% lower odds of having CAC=0 (odds ratio, 0.18 [95% CI, 0.09-0.37]) and had >4-fold higher odds of CAC≥1000 (odds ratio, 4.77 [95% CI, 2.88-7.88]). On a continuous scale, each SD increment increase in the polygenic risk score was associated with a 78% higher CAC score. Results were nearly identical using a second confirmatory polygenic CHD risk score in White participants.

Conclusions: Polygenic CHD risk is robustly associated with a lower prevalence of CAC=0 and a higher prevalence of CAC≥1000 in adults ≥75 years of age, beyond lifestyle and traditional risk factors. These results suggest a heritable contribution to distinct healthy and unhealthy arterial aging phenotypes that persist throughout the life course.

Keywords: aging; cardiovascular diseases; coronary artery disease; humans; prevalence.

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Conflict of interest statement

Dr Blaha reports grants from the National Institutes of Health, US Food and Drug Administration, American Heart Association, Amgen, Novo Nordisk, and Bayer, as well as Advisory Boards for Amgen, Novartis, Novo Nordisk, Bayer, Roche, Merck, Astra Zeneca, Eli Lilly, Boehringer Ingelheim, Vectura, Agepha. The other authors report no conflicts.

Comment in

References

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