| Title: | Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia |
| Journal: | JACC Advances |
| Published: | 28 Oct 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38938725/ |
| DOI: | https://doi.org/10.1016/j.jacadv.2023.100662 |
| Citations: | 2 (2 in last 2 years) as of 8 Aug 2024 |
Publication 9298
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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).</p>
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.</p>
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.</p>
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.</p>
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
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