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 Kanoni; Jochen Kruppa; Anubha Mahajan; Robert A. Scott; Christina Willenborg; 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 Hoffmann; Oddgeir L. Holmen; Kristian Hveem; Jan Håkan Jansson; Karl Heinz Jöckel; Thorsten Kessler; Jennifer Kriebel; Karl L. Laugwitz; Eirini Marouli; Nicola Martinelli; Mark I. McCarthy; Natalie R. Van Zuydam; Christa Meisinger; Tõnu Esko; Evelin Mihailov; Stefan A. Escher; Maris Alver; Susanne Moebus; Andrew D. Morris; Martina Müller-Nurasyid; Majid Nikpay; Oliviero Olivieri; Louis Philippe Lemieux Perreault; Alaa AlQarawi; Neil R. Robertson; Karen O. Akinsanya; Dermot F. Reilly; Thomas F. Vogt; Wu Yin; Folkert W. Asselbergs; Charles Kooperberg; Rebecca D. Jackson; Eli Stahl; Konstantin Strauch; Tibor V. Varga; Melanie Waldenberger; Lingyao Zeng; Aldi T. Kraja; Chunyu Liu; Georg B. Ehret; Christopher Newton-Cheh; Daniel I. Chasman; Rajiv Chowdhury; Marco Ferrario; Ian Ford; J. Wouter Jukema; Frank Kee; Kari Kuulasmaa; Børge G. Nordestgaard; Markus Perola; Danish Saleheen; Naveed Sattar; Praveen Surendran; David Tregouet; Robin Young; Joanna M.M. Howson; Adam S. Butterworth; John Danesh; Diego Ardissino; Erwin P. Bottinger; Raimund Erbel; Paul W. Franks; Domenico Girelli; Alistair S. Hall; G. Kees Hovingh; Adnan Kastrati; Wolfgang Lieb; Thomas Meitinger; William E. Kraus; Svati H. Shah; Ruth McPherson; Marju Orho-Melander; Olle Melander; Andres Metspalu; Colin N.A. Palmer; Annette Peters; Daniel J. Rader; Muredach P. Reilly; Ruth J.F. Loos; Alex P. Reiner; Dan M. Roden; Jean Claude Tardif; John R. Thompson; Nicholas J. Wareham; Hugh Watkins; Cristen J. Willer; Sekar Kathiresan; Panos Deloukas; Nilesh J. Samani; Heribert Schunkert

doi:10.1056/NEJMoa1507652

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 Willenborg, 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 Hoffmann, Oddgeir L. Holmen, Kristian Hveem, Jan Håkan Jansson, Karl Heinz Jöckel, Thorsten Kessler, Jennifer Kriebel, Karl L. Laugwitz, Eirini Marouli, Nicola Martinelli, Mark I. McCarthy, Natalie R. Van Zuydam, Christa Meisinger, Tõnu Esko, Evelin Mihailov, Stefan A. Escher, Maris Alver, Susanne Moebus, Andrew D. Morris, Martina Müller-Nurasyid, Majid Nikpay, Oliviero Olivieri, Louis Philippe Lemieux Perreault, Alaa AlQarawi, Neil R. Robertson, Karen O. Akinsanya, Dermot F. Reilly, Thomas F. Vogt, Wu Yin, Folkert W. Asselbergs, Charles Kooperberg, Rebecca D. Jackson, Eli Stahl, Konstantin Strauch, Tibor V. Varga, Melanie Waldenberger, Lingyao Zeng, Aldi T. Kraja, Chunyu Liu, Georg B. Ehret, Christopher Newton-Cheh, Daniel I. Chasman, Rajiv Chowdhury, Marco Ferrario, Ian Ford, J. Wouter Jukema, Frank Kee, Kari Kuulasmaa, Børge G. Nordestgaard, Markus Perola, Danish Saleheen, Naveed Sattar, Praveen Surendran, David Tregouet, Robin Young, Joanna M.M. Howson, Adam S. Butterworth, John Danesh, Diego Ardissino, Erwin P. Bottinger, Raimund Erbel, Paul W. Franks, Domenico Girelli, Alistair S. Hall, G. Kees Hovingh, Adnan Kastrati, Wolfgang Lieb, Thomas Meitinger, William E. Kraus, Svati H. Shah, Ruth McPherson, Marju Orho-Melander, Olle Melander, Andres Metspalu, Colin N.A. Palmer, Annette Peters, Daniel J. Rader, Muredach P. Reilly, Ruth J.F. Loos, Alex P. Reiner, Dan M. Roden, Jean Claude Tardif, John R. Thompson, Nicholas J. Wareham, Hugh Watkins, Cristen J. Willer, Sekar Kathiresan, Panos Deloukas, Nilesh J. Samani, Heribert Schunkert

School of Medicine

Research output: Contribution to journal › Article › peer-review

264 Scopus citations

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; minorallele 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 language	English (US)
Pages (from-to)	1134-1144
Number of pages	11
Journal	New England Journal of Medicine
Volume	374
Issue number	12
DOIs	https://doi.org/10.1056/NEJMoa1507652
State	Published - Mar 24 2016

ASJC Scopus subject areas

General Medicine

Access to Document

10.1056/NEJMoa1507652

Cite this

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., ... Schunkert, H. (2016). Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. New England Journal of Medicine, 374(12), 1134-1144. https://doi.org/10.1056/NEJMoa1507652

Stitziel, NO, Stirrups, KE, Masca, NGD, Erdmann, J, Ferrario, PG, König, IR, Weeke, PE, Webb, TR, Auer, PL, Schick, UM, Lu, Y, Zhang, H, Dube, MP, Goel, A, Farrall, M, Peloso, GM, Won, HH, Do, R, Van Iperen, E, Kanoni, S, Kruppa, J, Mahajan, A, Scott, RA, Willenborg, C, Braund, PS, Van Capelleveen, JC, Doney, ASF, Donnelly, LA, Asselta, R, Merlini, PA, Duga, S, Marziliano, N, Denny, JC, Shaffer, CM, El-Mokhtari, NE, Franke, A, Gottesman, O, Heilmann, S, Hengstenberg, C, Hoffmann, P, Holmen, OL, Hveem, K, Jansson, JH, Jöckel, KH, Kessler, T, Kriebel, J, Laugwitz, KL, Marouli, E, Martinelli, N, McCarthy, MI, Van Zuydam, NR, Meisinger, C, Esko, T, Mihailov, E, Escher, SA, Alver, M, Moebus, S, Morris, AD, Müller-Nurasyid, M, Nikpay, M, Olivieri, O, Perreault, LPL, AlQarawi, A, Robertson, NR, Akinsanya, KO, Reilly, DF, Vogt, TF, Yin, W, Asselbergs, FW, Kooperberg, C, Jackson, RD, Stahl, E, Strauch, K, Varga, TV, Waldenberger, M, Zeng, L, Kraja, AT, Liu, C, Ehret, GB, Newton-Cheh, C, Chasman, DI, Chowdhury, R, Ferrario, M, Ford, I, Jukema, JW, Kee, F, Kuulasmaa, K, Nordestgaard, BG, Perola, M, Saleheen, D, Sattar, N, Surendran, P, Tregouet, D, Young, R, Howson, JMM, Butterworth, AS, Danesh, J, Ardissino, D, Bottinger, EP, Erbel, R, Franks, PW, Girelli, D, Hall, AS, Hovingh, GK, Kastrati, A, Lieb, W, Meitinger, T, Kraus, WE, Shah, SH, McPherson, R, Orho-Melander, M, Melander, O, Metspalu, A, Palmer, CNA, Peters, A, Rader, DJ, Reilly, MP, Loos, RJF, Reiner, AP, Roden, DM, Tardif, JC, Thompson, JR, Wareham, NJ, Watkins, H, Willer, CJ, Kathiresan, S, Deloukas, P, Samani, NJ & Schunkert, H 2016, 'Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease', New England Journal of Medicine, vol. 374, no. 12, pp. 1134-1144. https://doi.org/10.1056/NEJMoa1507652

@article{c23b801a75a9472198b8df40d7a55c2a,

title = "Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease",

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; minorallele 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).",

author = "Stitziel, {Nathan O.} and Stirrups, {Kathleen E.} and Masca, {Nicholas G.D.} and Jeanette Erdmann and Ferrario, {Paola G.} and K{\"o}nig, {Inke R.} and Weeke, {Peter E.} and Webb, {Thomas R.} and Auer, {Paul L.} and Schick, {Ursula M.} and Yingchang Lu and He Zhang and Dube, {Marie Pierre} and Anuj Goel and Martin Farrall and Peloso, {Gina M.} and Won, {Hong Hee} and Ron Do and {Van Iperen}, Erik and Stavroula Kanoni and Jochen Kruppa and Anubha Mahajan and Scott, {Robert A.} and Christina Willenborg and Braund, {Peter S.} and {Van Capelleveen}, {Julian C.} and Doney, {Alex S.F.} and Donnelly, {Louise A.} and Rosanna Asselta and Merlini, {Piera A.} and Stefano Duga and Nicola Marziliano and Denny, {Josh C.} and Shaffer, {Christian M.} and El-Mokhtari, {Nour Eddine} and Andre Franke and Omri Gottesman and Stefanie Heilmann and Christian Hengstenberg and Per Hoffmann and Holmen, {Oddgeir L.} and Kristian Hveem and Jansson, {Jan H{\aa}kan} and J{\"o}ckel, {Karl Heinz} and Thorsten Kessler and Jennifer Kriebel and Laugwitz, {Karl L.} and Eirini Marouli and Nicola Martinelli and McCarthy, {Mark I.} and {Van Zuydam}, {Natalie R.} and Christa Meisinger and T{\~o}nu Esko and Evelin Mihailov and Escher, {Stefan A.} and Maris Alver and Susanne Moebus and Morris, {Andrew D.} and Martina M{\"u}ller-Nurasyid and Majid Nikpay and Oliviero Olivieri and Perreault, {Louis Philippe Lemieux} and Alaa AlQarawi and Robertson, {Neil R.} and Akinsanya, {Karen O.} and Reilly, {Dermot F.} and Vogt, {Thomas F.} and Wu Yin and Asselbergs, {Folkert W.} and Charles Kooperberg and Jackson, {Rebecca D.} and Eli Stahl and Konstantin Strauch and Varga, {Tibor V.} and Melanie Waldenberger and Lingyao Zeng and Kraja, {Aldi T.} and Chunyu Liu and Ehret, {Georg B.} and Christopher Newton-Cheh and Chasman, {Daniel I.} and Rajiv Chowdhury and Marco Ferrario and Ian Ford and Jukema, {J. Wouter} and Frank Kee and Kari Kuulasmaa and Nordestgaard, {B{\o}rge G.} and Markus Perola and Danish Saleheen and Naveed Sattar and Praveen Surendran and David Tregouet and Robin Young and Howson, {Joanna M.M.} and Butterworth, {Adam S.} and John Danesh and Diego Ardissino and Bottinger, {Erwin P.} and Raimund Erbel and Franks, {Paul W.} and Domenico Girelli and Hall, {Alistair S.} and Hovingh, {G. Kees} and Adnan Kastrati and Wolfgang Lieb and Thomas Meitinger and Kraus, {William E.} and Shah, {Svati H.} and Ruth McPherson and Marju Orho-Melander and Olle Melander and Andres Metspalu and Palmer, {Colin N.A.} and Annette Peters and Rader, {Daniel J.} and Reilly, {Muredach P.} and Loos, {Ruth J.F.} and Reiner, {Alex P.} and Roden, {Dan M.} and Tardif, {Jean Claude} and Thompson, {John R.} and Wareham, {Nicholas J.} and Hugh Watkins and Willer, {Cristen J.} and Sekar Kathiresan and Panos Deloukas and Samani, {Nilesh J.} and Heribert Schunkert",

note = "Publisher Copyright: Copyright {\textcopyright} 2016 Massachusetts Medical Society.",

year = "2016",

month = mar,

day = "24",

doi = "10.1056/NEJMoa1507652",

language = "English (US)",

volume = "374",

pages = "1134--1144",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "12",

}

TY - JOUR

T1 - Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease

AU - Stitziel, Nathan O.

AU - Stirrups, Kathleen E.

AU - Masca, Nicholas G.D.

AU - Erdmann, Jeanette

AU - Ferrario, Paola G.

AU - König, Inke R.

AU - Weeke, Peter E.

AU - Webb, Thomas R.

AU - Auer, Paul L.

AU - Schick, Ursula M.

AU - Lu, Yingchang

AU - Zhang, He

AU - Dube, Marie Pierre

AU - Goel, Anuj

AU - Farrall, Martin

AU - Peloso, Gina M.

AU - Won, Hong Hee

AU - Do, Ron

AU - Van Iperen, Erik

AU - Kanoni, Stavroula

AU - Kruppa, Jochen

AU - Mahajan, Anubha

AU - Scott, Robert A.

AU - Willenborg, Christina

AU - Braund, Peter S.

AU - Van Capelleveen, Julian C.

AU - Doney, Alex S.F.

AU - Donnelly, Louise A.

AU - Asselta, Rosanna

AU - Merlini, Piera A.

AU - Duga, Stefano

AU - Marziliano, Nicola

AU - Denny, Josh C.

AU - Shaffer, Christian M.

AU - El-Mokhtari, Nour Eddine

AU - Franke, Andre

AU - Gottesman, Omri

AU - Heilmann, Stefanie

AU - Hengstenberg, Christian

AU - Hoffmann, Per

AU - Holmen, Oddgeir L.

AU - Hveem, Kristian

AU - Jansson, Jan Håkan

AU - Jöckel, Karl Heinz

AU - Kessler, Thorsten

AU - Kriebel, Jennifer

AU - Laugwitz, Karl L.

AU - Marouli, Eirini

AU - Martinelli, Nicola

AU - McCarthy, Mark I.

AU - Van Zuydam, Natalie R.

AU - Meisinger, Christa

AU - Esko, Tõnu

AU - Mihailov, Evelin

AU - Escher, Stefan A.

AU - Alver, Maris

AU - Moebus, Susanne

AU - Morris, Andrew D.

AU - Müller-Nurasyid, Martina

AU - Nikpay, Majid

AU - Olivieri, Oliviero

AU - Perreault, Louis Philippe Lemieux

AU - AlQarawi, Alaa

AU - Robertson, Neil R.

AU - Akinsanya, Karen O.

AU - Reilly, Dermot F.

AU - Vogt, Thomas F.

AU - Yin, Wu

AU - Asselbergs, Folkert W.

AU - Kooperberg, Charles

AU - Jackson, Rebecca D.

AU - Stahl, Eli

AU - Strauch, Konstantin

AU - Varga, Tibor V.

AU - Waldenberger, Melanie

AU - Zeng, Lingyao

AU - Kraja, Aldi T.

AU - Liu, Chunyu

AU - Ehret, Georg B.

AU - Newton-Cheh, Christopher

AU - Chasman, Daniel I.

AU - Chowdhury, Rajiv

AU - Ferrario, Marco

AU - Ford, Ian

AU - Jukema, J. Wouter

AU - Kee, Frank

AU - Kuulasmaa, Kari

AU - Nordestgaard, Børge G.

AU - Perola, Markus

AU - Saleheen, Danish

AU - Sattar, Naveed

AU - Surendran, Praveen

AU - Tregouet, David

AU - Young, Robin

AU - Howson, Joanna M.M.

AU - Butterworth, Adam S.

AU - Danesh, John

AU - Ardissino, Diego

AU - Bottinger, Erwin P.

AU - Erbel, Raimund

AU - Franks, Paul W.

AU - Girelli, Domenico

AU - Hall, Alistair S.

AU - Hovingh, G. Kees

AU - Kastrati, Adnan

AU - Lieb, Wolfgang

AU - Meitinger, Thomas

AU - Kraus, William E.

AU - Shah, Svati H.

AU - McPherson, Ruth

AU - Orho-Melander, Marju

AU - Melander, Olle

AU - Metspalu, Andres

AU - Palmer, Colin N.A.

AU - Peters, Annette

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Loos, Ruth J.F.

AU - Reiner, Alex P.

AU - Roden, Dan M.

AU - Tardif, Jean Claude

AU - Thompson, John R.

AU - Wareham, Nicholas J.

AU - Watkins, Hugh

AU - Willer, Cristen J.

AU - Kathiresan, Sekar

AU - Deloukas, Panos

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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; minorallele 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).

AB - 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; minorallele 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).

UR - http://www.scopus.com/inward/record.url?scp=84962230620&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962230620&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1507652

DO - 10.1056/NEJMoa1507652

M3 - Article

C2 - 26934567

AN - SCOPUS:84962230620

SN - 0028-4793

VL - 374

SP - 1134

EP - 1144

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 12

ER -

Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this