Dataset Information

Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.

ABSTRACT: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease.To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD).In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305?699 individuals of the Global Lipids Genetics Consortium and up to 120?600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis.Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels.Circulating lipid levels and CAD.Among 46?891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32?646 control participants (0.32%) and 83 of 14?245 participants with early-onset CAD (0.58%). Compared with 46?703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio?=?1.84; 95% CI, 1.35-2.51; P?

SUBMITTER: Khera AV

PROVIDER: S-EPMC5664181 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.

Khera Amit V AV Won Hong-Hee HH Peloso Gina M GM O'Dushlaine Colm C Liu Dajiang D Stitziel Nathan O NO Natarajan Pradeep P Nomura Akihiro A Emdin Connor A CA Gupta Namrata N Borecki Ingrid B IB Asselta Rosanna R Duga Stefano S Merlini Piera Angelica PA Correa Adolfo A Kessler Thorsten T Wilson James G JG Bown Matthew J MJ Hall Alistair S AS Braund Peter S PS Carey David J DJ Murray Michael F MF Kirchner H Lester HL Leader Joseph B JB Lavage Daniel R DR Manus J Neil JN Hartzel Dustin N DN Samani Nilesh J NJ Schunkert Heribert H Marrugat Jaume J Elosua Roberto R McPherson Ruth R Farrall Martin M Watkins Hugh H Lander Eric S ES Rader Daniel J DJ Danesh John J Ardissino Diego D Gabriel Stacey S Willer Cristen C Abecasis Gonçalo R GR Saleheen Danish D Dewey Frederick E FE Kathiresan Sekar S

JAMA 20170301 9

<h4>Importance</h4>The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease.<h4>Objective</h4>To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD).<h4>Design, setting, and participants</h4>In a cr ...[more]

PMID: 28267856

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Project description:Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT)-SNVs might present one potential source of this “missing heritability”. Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD = 20,405), and a more inclusive (angina and chronic ischemic heart disease; SOFT = 34,782). Results: In HARD cases, the most significant (p < 0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR = 1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR = 0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing corrections (at FDR < 5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active, and their average body height was ~2.00 cm lower compared to controls; both traits are known to be related to increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (p < 0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3), and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (p < 0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT-SNV data in even larger study cohorts may be needed to conclusively determine the role of MT DNA in CAD.

Dataset Information

Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.

Publications

Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.

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