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Published on: August 28, 2018
Polygenic Risk Scores and Extreme Coronary Artery Calcium Phenotypes (CAC=0 and CAC≥1000) in Adults ≥75 Years Old:
Omar Dzaye1, Alexander C Razavi1,2, Zeina A Dardari1
1Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (O.D., A.C.R., Z.A.D., S.P.W., M.B.M., M.J.B.).
Insights
Genetic risk scores for coronary heart disease (CHD) significantly predict coronary artery calcium (CAC) in older adults. Higher polygenic risk is linked to less CAC=0 and more CAC≥1000, indicating heritable arterial aging patterns.
Area of Science:
- Cardiovascular Disease Research
- Genetics and Genomics
- Aging Research
Background:
- Coronary artery calcium (CAC) heterogeneity in older adults is not fully explained by traditional risk factors.
- Subclinical atherosclerosis burden extremes correlate with 10-year atherosclerotic cardiovascular disease risk.
- Genetic factors influencing arterial aging remain largely unknown.
Purpose of the Study:
- To investigate the association of two polygenic scores for coronary heart disease (CHD) with CAC in adults aged 75 and older.
- To determine if genetic predisposition independently predicts CAC burden in advanced age.
Main Methods:
- Utilized data from 1865 Atherosclerosis Risk in Communities (ARIC) study participants with genetic testing and CAC scans.
- Calculated externally derived and ARIC-derived polygenic CHD risk scores.
- Employed multivariable logistic regression, adjusting for lifestyle, traditional risk factors, and local ancestry.
Main Results:
- Individuals in the highest polygenic CHD risk quartile (>80th percentile) had 82% lower odds of CAC=0 and over 4-fold higher odds of CAC≥1000 compared to the lowest quartile (<20th percentile).
- Each standard deviation increase in polygenic risk score correlated with a 78% increase in continuous CAC.
- Findings were consistent across different polygenic risk score calculations and ancestral groups.
Conclusions:
- Polygenic CHD risk is a strong predictor of CAC prevalence (CAC=0 and CAC≥1000) in adults ≥75 years.
- Genetic factors contribute significantly to distinct healthy and unhealthy arterial aging phenotypes.
- These genetic influences on arterial aging persist throughout the life course.
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.
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