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 Ejvin Weeke; Thomas R Webb; Paul L Auer; Ursula M Schick; Yingchang Lu; He Zhang; Marie-Pierre Dubé; Anuj Goel; Martin Farrall; Gina M Peloso; Hong-Hee Won; Ron Do; Erik P A van Iperen; Stavroula Kanoni; Jochen 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-Heimbach; Christian Hengstenberg; Per Hoffman; Oddgeir L Holmen; Kristian Hveem; Jan-Håkan Jansson; Karl-Heinz Jöckel; Thorsten Kessler; Jennifer Kriebel; Karl-Ludwig Laugwitz; Eirini Marouli; Nicola Martinelli; Børge G Nordestgaard; Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

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 Ejvin Weeke, Thomas R Webb, Paul L Auer, Ursula M Schick, Yingchang Lu, He Zhang, Marie-Pierre Dubé, Anuj Goel, Martin Farrall, Gina M Peloso, Hong-Hee Won, Ron Do, Erik P A 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-Heimbach, Christian Hengstenberg, Per Hoffman, Oddgeir L Holmen, Kristian Hveem, Jan-Håkan Jansson, Karl-Heinz Jöckel, Thorsten Kessler, Jennifer Kriebel, Karl-Ludwig Laugwitz, Eirini Marouli, Nicola Martinelli, Børge G Nordestgaard, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

Department of Clinical Medicine

264 Citations (Scopus)

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 language	English
Journal	New England Journal of Medicine
Volume	374
Issue number	12
Pages (from-to)	1134-1144
Number of pages	11
ISSN	0028-4793
DOIs	https://doi.org/10.1056/nejmoa1507652
Publication status	Published - 24 Mar 2016

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

UN SDGs

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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., Dubé, M-P., Goel, A., Farrall, M., Peloso, G. M., Won, H-H., Do, R., van Iperen, E. P. A., ... 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), 1134-1144. 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, Dubé, M-P, Goel, A, Farrall, M, Peloso, GM, Won, H-H, Do, R, van Iperen, EPA, Kanoni, S, Kruppa, J, Mahajan, A, Scott, RA, Willenberg, 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-Heimbach, S, Hengstenberg, C, Hoffman, P, Holmen, OL, Hveem, K, Jansson, J-H, Jöckel, K-H, Kessler, T, Kriebel, J, Laugwitz, K-L, Marouli, E, Martinelli, N, Nordestgaard, BG & 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, vol. 374, no. 12, pp. 1134-1144. https://doi.org/10.1056/nejmoa1507652

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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; 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.).",

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",

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 Ejvin} and Webb, {Thomas R} and Auer, {Paul L} and Schick, {Ursula M} and Yingchang Lu and He Zhang and Marie-Pierre Dub{\'e} and Anuj Goel and Martin Farrall and Peloso, {Gina M} and Hong-Hee Won and Ron Do and {van Iperen}, {Erik P A} and Stavroula Kanoni and Jochen Kruppa and Anubha Mahajan and Scott, {Robert A} and Christina Willenberg 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-Heimbach and Christian Hengstenberg and Per Hoffman and Holmen, {Oddgeir L} and Kristian Hveem and Jan-H{\aa}kan Jansson and Karl-Heinz J{\"o}ckel and Thorsten Kessler and Jennifer Kriebel and Karl-Ludwig Laugwitz and Eirini Marouli and Nicola Martinelli and Nordestgaard, {B{\o}rge G} and {Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators}",

year = "2016",

month = mar,

day = "24",

doi = "10.1056/nejmoa1507652",

language = "English",

volume = "374",

pages = "1134--1144",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "12",

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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 Ejvin

AU - Webb, Thomas R

AU - Auer, Paul L

AU - Schick, Ursula M

AU - Lu, Yingchang

AU - Zhang, He

AU - Dubé, Marie-Pierre

AU - Goel, Anuj

AU - Farrall, Martin

AU - Peloso, Gina M

AU - Won, Hong-Hee

AU - Do, Ron

AU - van Iperen, Erik P A

AU - Kanoni, Stavroula

AU - Kruppa, Jochen

AU - Mahajan, Anubha

AU - Scott, Robert A

AU - Willenberg, 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-Heimbach, Stefanie

AU - Hengstenberg, Christian

AU - Hoffman, 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-Ludwig

AU - Marouli, Eirini

AU - Martinelli, Nicola

AU - Nordestgaard, Børge G

AU - Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

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; 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.).

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; 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.).

KW - Aged

KW - Angiopoietins

KW - Cell Adhesion Molecules

KW - Coronary Artery Disease

KW - Female

KW - Genotyping Techniques

KW - Humans

KW - Lipoprotein Lipase

KW - Male

KW - Middle Aged

KW - Mutation

KW - Mutation, Missense

KW - Risk Factors

KW - Sequence Analysis, DNA

KW - Triglycerides

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/nejmoa1507652

DO - 10.1056/nejmoa1507652

M3 - Journal article

C2 - 26934567

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

Keywords

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