| Title: | Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia |
| Journal: | JACC Advances |
| Published: | 1 Nov 2023 |
| DOI: | https://doi.org/10.1016/j.jacadv.2023.100662 |
Publication 9298
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Background Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder characterized by increased circulating low-density lipoprotein cholesterol and accelerated atherosclerosis. Even among this high-risk group, prior studies note considerable variability in risk of coronary artery disease (CAD). Objectives The purpose of this study was to evaluate the cumulative impact of many common DNA variants - as quantified by a polygenic score - on incident CAD among individuals carrying a HeFH variant. Methods We analyzed data from a prospective cohort study of 1,315 individuals who carried a HeFH variant and 1,315 matched family noncarriers derived from a nationwide screening program in the Netherlands, with subsequent replication in 151,009 participants of the UK Biobank. Results Despite identification and lipid management within the Dutch screening program, 84 (6.4%) of HeFH variant carriers developed CAD as compared to 45 (3.4%) of matched family members (median follow-up 10.2 years, HR 1.88, 95% CI: 1.31-2.70). Among HeFH variant carriers, a polygenic score was associated with CAD with an effect size similar to low-density lipoprotein cholesterol - HR of 1.35 (95% CI: 1.07-1.70) and 1.41 (95% CI: 1.17-1.70) per standard deviation increase, respectively. When compared to noncarriers, CAD risk increased from 1.24-fold (95% CI: 0.64-2.34) to 3.37-fold (95% CI: 2.11-5.36) across quintiles of the polygenic score. A similar risk gradient, 1.36-fold (95% CI: 0.65-2.85) to 2.88-fold (95% CI: 1.59-5.20), was observed in 429 carriers in the UK Biobank. Conclusions In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.</p>
11 Authors
- Laurens F. Reeskamp
- Injeong Shim
- Jacqueline S. Dron
- Shirin Ibrahim
- Tycho R. Tromp
- Akl C. Fahed
- Aniruddh P. Patel
- Barbara A. Hutten
- Erik S.G. Stroes
- G. Kees Hovingh
- Amit V. Khera
Enabling scientific discoveries that improve human health