Stitziel, N. O. et al. (2016) Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. New England Journal of Medicine, 374(12), pp. 1134-1144. (doi: 10.1056/NEJMoa1507652) (PMID:26934567) (PMCID:PMC4850838)
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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.).
| Item Type: | Articles |
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| Additional Information: | A correction to this article is available at http://dx.doi.org/10.1056/NEJMxx160012. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Young, Dr Robin and Sattar, Professor Naveed and Ford, Professor Ian |
| Authors: | Stitziel, N. O., Stirrups, K. E., Masca, N. G.D., Erdmann, J., Ferrario, P. G., König, I. R., Weeke, P. E., Webb, T. R., Auer, P. L., Schick, U. M., Lu, Y., Zhang, H., Dube, M.-P., Goel, A., Farrall, M., Peloso, G. M., Won, H.-H., Do, R., van Iperen, E., Kanoni, S., Kruppa, J., Mahajan, A., Scott, R. A., Willenborg, C., Braund, P. S., van Capelleveen, J. C., Doney, A. S.F., Donnelly, L. A., Asselta, R., Merlini, P. A., Duga, S., Marziliano, N., Denny, J. C., Shaffer, C. M., El-Mokhtari, N. E., Franke, A., Gottesman, O., Heilmann, S., Hengstenberg, C., Hoffmann, P., Holmen, O. L., Hveem, K., Jansson, J.-H., Jöckel, K.-H., Kessler, T., Kriebel, J., Laugwitz, K. L., Marouli, E., Martinelli, N., McCarthy, M. I., Van Zuydam, N. R., Meisinger, C., Esko, T., Mihailov, E., Escher, S. A., Alver, M., Moebus, S., Morris, A. D., Müller-Nurasyid, M., Nikpay, M., Olivieri, O., Lemieux Perreault, L.-P., AlQarawi, A., Robertson, N. R., Akinsanya, K. O., Reilly, D. F., Vogt, T. F., Yin, W., Asselbergs, F. W., Kooperberg, K. O., Jackson, R. D., Stahl, E., Strauch, K., Varga, T. V., Waldenberger, M., Zeng, L., Kraja, A. T., Liu, C., Ehret, G. B., Newton-Cheh, C., Chasman, D. I., Chowdhury, R., Ferrario, M., Ford, I., Jukema, J. W., Kee, F., Kuulasmaa, K., Nordestagaard, B. G., Perola, M., Saleheen, D., Sattar, N., Surendran, P., Tregouet, D., Young, R., Howson, J. M.M., Butterworth, A. S., Danesh, J., Ardissino, D., Bottinger, E. P., Erbel, R., Franks, P. W., Girelli, D., Hall, A. S., Hovingh, G. K., Kastrati, A., Lieb, W., Meitinger, T., Kraus, W. E., Shah, S. H., McPherson, R., Orho-Melander, M., Melander, O., Metspalu, A., Palmer, C. N.A., Peters, A., Rader, D. J., Reilly, M. P., Loos, R. J.F., Reiner, A. P., Roden, D. M., Tardif, J.-C., Thompson, J. R., Wareham, N. J., Watkins, H., Willer, C. J., Kathiresan, S., Deloukas, P., Samani, N. J., and Schunkert, H. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre |
| Journal Name: | New England Journal of Medicine |
| Publisher: | Massachusetts Medical Society |
| ISSN: | 0028-4793 |
| ISSN (Online): | 1533-4406 |
| Published Online: | 02 March 2016 |
| Copyright Holders: | Copyright © 2016 Massachusetts Medical Society |
| First Published: | First published in New England Journal of Medicine 374(12): 1134-1144 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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