Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 374, Issue 12, Pages 1134-1144Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1507652
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Funding
- National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) [K08HL114642]
- Foundation for Barnes Jewish Hospital
- National Heart, Lung, and Blood Institute of the NIH [K01HL125751]
- Massachusetts General Hospital
- Donovan Family Foundation
- NIH [R01HL107816, R01HL127564]
- Fondation Leducq
- Merck
- Italian Ministry of Health [RFPS-2007-3-644382]
- Regione Emilia Romagna Area
- Wellcome Trust [090532/Z/09/Z, 098381]
- British Heart Foundation (BHF) Centre of Research Excellence
- National Cancer Institute [R25CA094880]
- EU FP7 AMP
- Wellcome Trust Institutional
- National Institute for Health Research (NIHR)
- British Heart Foundation
- NIHR Leicester Cardiovascular Biomedical Research Unit (BRU)
- BRU
- American Heart Association [15POST23280019]
- European Union [261123]
- Fondation Leducq (CADgenomics) [12CVD02]
- German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME)
- Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces
- SFB [1123]
- DZHK
- BHF [RG/14/5/30893]
- British Heart Foundation [RG/13/13/30194, RG/14/5/30893, RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [G0800270, MC_UU_12015/1, MR/N005813/1, MC_PC_13048, MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10099, NF-SI-0512-10165, NF-SI-0611-10170] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0016320, NNF14OC0011049, NNF16OC0021370] Funding Source: researchfish
- MRC [MR/L003120/1, MR/N005813/1, MC_UU_12015/1, G0800270] Funding Source: UKRI
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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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