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Open Access Green as soon as Postprint is submitted to ZB.
Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease.
N. Engl. J. Med. 374, 1134-1144 (2016)
BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Of-function Mutations; Lipoprotein-lipase; Artery-disease; Heart-disease; Pcsk9; Triglycerides; Inhibition; Variant; Apoc3; Hdl
Language
english
Publication Year
2016
HGF-reported in Year
2016
ISSN (print) / ISBN
0028-4793
e-ISSN
1533-4406
Quellenangaben
Volume: 374,
Issue: 12,
Pages: 1134-1144
Publisher
Massachusetts Medical Society (MMS)
Publishing Place
Waltham
Reviewing status
Peer reviewed
Institute(s)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
POF-Topic(s)
30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-504091-002
G-504100-001
G-504091-001
G-501900-402
G-504000-006
G-500700-001
G-504100-001
G-504091-001
G-501900-402
G-504000-006
G-500700-001
WOS ID
WOS:000372585100006
Scopus ID
84962230620
Erfassungsdatum
2016-04-20