Dataset Information

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

ABSTRACT: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.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.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)).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.).

SUBMITTER: Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

PROVIDER: S-EPMC4850838 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Stitziel Nathan O NO Stirrups Kathleen E KE Masca Nicholas G D NG Erdmann Jeanette J Ferrario Paola G PG König Inke R IR Weeke Peter E PE Webb Thomas R TR Auer Paul L PL Schick Ursula M UM Lu Yingchang Y Zhang He H Dube Marie-Pierre MP Goel Anuj A Farrall Martin M Peloso Gina M GM Won Hong-Hee HH Do Ron R van Iperen Erik E Kanoni Stavroula S Kruppa Jochen J Mahajan Anubha A Scott Robert A RA Willenberg Christina C Braund Peter S PS van Capelleveen Julian C JC Doney Alex S F AS Donnelly Louise A LA Asselta Rosanna R Merlini Piera A PA Duga Stefano S Marziliano Nicola N Denny Josh C JC Shaffer Christian M CM El-Mokhtari Nour Eddine NE Franke Andre A Gottesman Omri O Heilmann Stefanie S Hengstenberg Christian C Hoffman Per P Holmen Oddgeir L OL Hveem Kristian K Jansson Jan-Håkan JH Jöckel Karl-Heinz KH Kessler Thorsten T Kriebel Jennifer J Laugwitz Karl L KL Marouli Eirini E Martinelli Nicola N McCarthy Mark I MI Van Zuydam Natalie R NR Meisinger Christa C Esko Tõnu T Mihailov Evelin E Escher Stefan A SA Alver Maris M Moebus Susanne S Morris Andrew D AD Müller-Nurasyid Martina M Nikpay Majid M Olivieri Oliviero O Lemieux Perreault Louis-Philippe LP AlQarawi Alaa A Robertson Neil R NR Akinsanya Karen O KO Reilly Dermot F DF Vogt Thomas F TF Yin Wu W Asselbergs Folkert W FW Kooperberg Charles C Jackson Rebecca D RD Stahl Eli E Strauch Konstantin K Varga Tibor V TV Waldenberger Melanie M Zeng Lingyao L Kraja Aldi T AT Liu Chunyu C Ehret George B GB Newton-Cheh Christopher C Chasman Daniel I DI Chowdhury Rajiv R Ferrario Marco M Ford Ian I Jukema J Wouter JW Kee Frank F Kuulasmaa Kari K Nordestgaard Børge G BG Perola Markus M Saleheen Danish D Sattar Naveed N Surendran Praveen P Tregouet David D Young Robin R Howson Joanna M M JM Butterworth Adam S AS Danesh John J Ardissino Diego D Bottinger Erwin P EP Erbel Raimund R Franks Paul W PW Girelli Domenico D Hall Alistair S AS Hovingh G Kees GK Kastrati Adnan A Lieb Wolfgang W Meitinger Thomas T Kraus William E WE Shah Svati H SH McPherson Ruth R Orho-Melander Marju M Melander Olle O Metspalu Andres A Palmer Colin N A CN Peters Annette A Rader Daniel D Reilly Muredach P MP Loos Ruth J F RJ Reiner Alex P AP Roden Dan M DM Tardif Jean-Claude JC Thompson John R JR Wareham Nicholas J NJ Watkins Hugh H Willer Cristen J CJ Kathiresan Sekkar S Deloukas Panos P Samani Nilesh J NJ Schunkert Heribert H

The New England journal of medicine 20160302 12

<h4>Background</h4>The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.<h4>Methods</h4>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.<h4>Resu ...[more]

PMID: 26934567

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Project description:Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys.We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels.Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).

Project description:ImportanceTriglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.ObjectiveTo compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.Design, setting, and participantsMendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.ExposuresDifferences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.Main outcomes and measuresOdds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins.ResultsA total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20).Conclusions and relevanceTriglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.

Project description:BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Dataset Information

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

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

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