期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 67, 期 22, 页码 2578-2589出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2016.03.520
关键词
coronary artery disease; gene sequencing; genetics; low-density lipoprotein cholesterol
资金
- British Heart Foundation [RG/13/13/30194]
- U.K. Medical Research Council [MR/L003120/1]
- Wellcome Trust
- EU Framework 6-Bloodomics Integrated Project
- Pfizer
- Novartis
- Merck
- U.K. National Institute for Health Research Cambridge Biomedical Research Centre
- European Research Council [268834]
- European Commission Framework Programme 7 [HEALTH-F2-2012-279233]
- National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]
- National Institute on Minority Health and Health Disparities
- German Federal Ministry of Education and Research (BMBF)
- European Union [261123]
- Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes) [12CVD02]
- Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces
- National Institutes of Health through the American Recovery and Reinvestment Act [5RC2HL102419]
- NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268200800007C]
- Boston University [N01-HC-25195]
- Affymetrix, Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- National Institute on Aging [R01AG023629]
- Programma di ricerca Regione-Universita Area 1-Strategic Programmes-Regione Emilia-Romagna
- American College of Cardiology/Merck Fellowship award
- Amarin Corporation
- National Heart, Lung, and Blood Institute award [K01HL125751]
- Deutsches Zentrum fur Herz-Kreislauf-Forschung rotation grant
- Zoll LifeCor
- Johnson Johnson
- Aegerion Pharmaceuticals
- Alnylam Pharmaceuticals
- Eli Lilly and Company
- Sanofi
- AstraZeneca
- Boehringer Ingelheim
- Bayer
- Daiichi-Sankyo
- GlaxoSmithKline
- Boston Scientific
- Bristol-Myers Squibb
- Menarini Group
- National Institutes of Health
- Massachusetts General Hospital
- Donovan Family Foundation
- Bayer Healthcare
- Regeneron Pharmaceuticals
- Leerink Partners
- Noble Insights
- Quest Diagnostics
- Genomics PLC
- [SFB 1123]
- [RFPS-2007-3-644382]
- [RC2 HL103010]
- [RC2 HL102923]
- [RC2 HL102924]
- [5U54HG003067]
- [R01 HL127564]
- [N01HC55222]
- [N01HC85079]
- [N01HC85080]
- [N01HC85081]
- [N01HC85082]
- [N01HC85083]
- [N01HC85086]
- [U01HL080295]
- [R01HL087652]
- [R01HL105756]
- [R01HL103612]
- [R01HL120393]
- MRC [MR/L003120/1] Funding Source: UKRI
- British Heart Foundation [RG/13/13/30194] Funding Source: researchfish
- Medical Research Council [MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10087] Funding Source: researchfish
BACKGROUND Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol >= 190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. OBJECTIVES This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. METHODS Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. RESULTS Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol >= 190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol >= 190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol >= 190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. CONCLUSIONS Among participants with LDL cholesterol >= 190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD. (C) 2016 by the American College of Cardiology Foundation.
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