TY - JOUR
T1 - Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia
AU - Reeskamp, Laurens F.
AU - Shim, Injeong
AU - Dron, Jacqueline S.
AU - Ibrahim, Shirin
AU - Tromp, Tycho R.
AU - Fahed, Akl C.
AU - Patel, Aniruddh P.
AU - Hutten, Barbara A.
AU - Stroes, Erik S.G.
AU - Hovingh, G. Kees
AU - Khera, Amit V.
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - Familial Hypercholesterolemia
KW - UK Biobank
KW - coronary artery disease
KW - low-density lipoprotein cholesterol
KW - polygenic risk
UR - http://www.scopus.com/inward/record.url?scp=85180173738&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jacadv.2023.100662
DO - https://doi.org/10.1016/j.jacadv.2023.100662
M3 - Article
SN - 2772-963X
VL - 2
JO - JACC: Advances
JF - JACC: Advances
IS - 9
M1 - 100662
ER -