Heterozygous <i>ABCG5</i> Gene Deficiency and Risk of Coronary Artery Disease.
Won, Hong Hee
Peloso, Gina M
Bown, Matthew J
Samani, Nilesh J
Shah, Svati H
Rader, Daniel J
Khera, Amit V
Circulation. Genomic and precision medicine
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Nomura, A., Emdin, C. A., Won, H. H., Peloso, G. M., Natarajan, P., Ardissino, D., Danesh, J., et al. (2020). Heterozygous <i>ABCG5</i> Gene Deficiency and Risk of Coronary Artery Disease.. Circulation. Genomic and precision medicine, 13 (5), 417-423. https://doi.org/10.1161/circgen.119.002871
BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8-as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8. RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; P=1.1×10-6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
This study was funded by the National Institutes of Health (R01 HL127564 and 5UM1HG008895). Exome sequencing in ATVB (Italian Atherosclerosis Thrombosis and Vascular Biology study), PROCARDIS (Precocious Coronary Artery Disease study), OHS (Ottawa Heart Study), PROMIS (Pakistan Risk of Myocardial Infarction Study), Leicester, Lubeck was supported by 5U54HG003067 to Dr Gabriel. The ATVB Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010-2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. Funding for the ESP-EOMI (Exome Sequencing Project Early-Onset Myocardial Infarction study) was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP [Women's Health Initiative Exome Sequencing Project]). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. The authors also wish to thank the staffs and participants of the JHS. The REGICOR study (Registre Gironi del COR study) was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER [European regional development fund, le fonds europeen de developpement regional]), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). Dr Peloso is supported by K01HL125751 and R03HL141439.
External DOI: https://doi.org/10.1161/circgen.119.002871
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315239
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Licence URL: https://creativecommons.org/licenses/by-nc/4.0/