Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Nathan O Stitziel, Kathleen E Stirrups, Nicholas G D Masca, Jeanette Erdmann, Paola G Ferrario, Inke R König, Peter E Weeke, Thomas R Webb, Paul L Auer, Ursula M Schick, Yingchang Lu, He Zhang, Marie-Pierre Dube, Anuj Goel, Martin Farrall, Gina M Peloso, Hong-Hee Won, Ron Do, Erik van Iperen, Stavroula KanoniJochen Kruppa, Anubha Mahajan, Robert A Scott, Christina Willenberg, Peter S Braund, Julian C van Capelleveen, Alex S F Doney, Louise A Donnelly, Rosanna Asselta, Piera A Merlini, Stefano Duga, Nicola Marziliano, Josh C Denny, Christian M Shaffer, Nour Eddine El-Mokhtari, Andre Franke, Omri Gottesman, Stefanie Heilmann, Christian Hengstenberg, Per Hoffman, Oddgeir L Holmen, Kristian Hveem, Jan-Håkan Jansson, Karl-Heinz Jöckel, Thorsten Kessler, Jennifer Kriebel, Karl L Laugwitz, Eirini Marouli, Neil R Robertson, John R Thompson, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

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Abstract

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=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-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=2.0×10(-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=2.5×10(-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. (Funded by the National Institutes of Health and others.).

Original languageEnglish
Pages (from-to)1134-44
Number of pages11
JournalNew England Journal of Medicine
Volume374
Issue number12
DOIs
Publication statusPublished - 24 Mar 2016

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Keywords

  • Aged
  • Angiopoietins
  • Cell Adhesion Molecules
  • Coronary Artery Disease
  • Female
  • Genotyping Techniques
  • Humans
  • Lipoprotein Lipase
  • Male
  • Middle Aged
  • Mutation
  • Mutation, Missense
  • Risk Factors
  • Sequence Analysis, DNA
  • Triglycerides
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Stitziel, N. O., Stirrups, K. E., Masca, N. G. D., Erdmann, J., Ferrario, P. G., König, I. R., ... Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators (2016). Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. New England Journal of Medicine, 374(12), 1134-44. https://doi.org/10.1056/NEJMoa1507652