Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia.

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.
Competing Interests: Funding support was provided by a grant from Stichting Atheros (to Dr Reeskamp), a grant HI19C1328 of the Korea Health Technology R&D Project through the 10.13039/501100003710Korea Health Industry Development Institute (KHIDI), funded by the 10.13039/501100003625Ministry of Health & Welfare, Republic of Korea (to Shim), grants 1K08HG010155 and 1U01HG011719 (to Dr Khera) from the 10.13039/100000051National Human Genome Research Institute, a Hassenfeld Scholar Award from 10.13039/100005294Massachusetts General Hospital (to Dr Khera), a Merkin Institute Fellowship from the Broad Institute of MIT and Harvard (to Dr Khera), and a sponsored research agreement from IBM Research (Dr Khera). Dr Reeskamp is co-founder of Lipid Tools B.V.; and reports speaker fee from Ultragenyx, Daiichi Sankyo, and Novartis. Dr Fahed is a consultant for and holds equity in Goodpath; and has received a research grant from Abbott Inc. Dr Hutten has received a research grant from Silence Therapeutics. Dr Stroes has received ad-board/lecturing fees paid to his institution by Sanofi/Regeneron, Esperion, Amgen, Novartis, Novo Nordisk, and Athera. Dr Hovingh has received research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, EU, and the Klinkerpad fonds; institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; Speakers Bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment at Novo Nordisk, Denmark since April, 2019. Dr Khera is an employee of Verve Therapeutics; has served as a scientific advisor to Amgen, Novartis, Silence Therapeutics, Korro Bio, Veritas International, Color Health, Third Rock Ventures, Illumina, Ambry, and Foresite Labs; holds equity in Verve Therapeutics, Color Health, and Foresite Labs; and is listed as a co-inventor on patent applications related to assessment and mitigation of risk associated with perturbations in body fat distribution. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2023 The Authors.)