Genome-Wide Association Study of Lp-PLA2 Activity and Mass in the Framingham Heart Study

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Abstract

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA ₂ activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA ₂ activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA ₂ activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10 ⁻²⁴); CELSR2/PSRC1 on chromosome 1 (p = 3×10 ⁻¹⁵); SCARB1 on chromosome 12 (p = 1×10 ⁻⁸) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10 ⁻⁸). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA ₂ mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA ₂ activity and mass.

Author Summary

Blood levels of lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂) show a strong association with atherosclerosis in humans. This enzyme is made by certain cells of the immune system, associates with lipoproteins (HDL and LDL), and is thought to be involved in inflammation. Studies have shown that Lp-PLA ₂ is a good predictor of cardiovascular disease, independent of HDL and LDL cholesterol levels. This has led to the development of drugs aimed at inhibiting Lp-PLA ₂ as a way to treat or prevent cardiovascular disease. The activity and mass of Lp-PLA ₂ are heritable traits, but major genetic determinants have not been explored in a systematic fashion. We examined genetic variants across the human genome to identify genes influencing Lp-PLA ₂ activity and mass. We studied 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genetic data on 550,000 genetic variants were available for association analysis. There was no overlap in the most significantly associated SNPs for activity and mass. We identified four distinct gene regions showing highly significant associations with Lp-PLA ₂ activity, all of which are known to include genes involved in cholesterol metabolism. The only locus associated with Lp-PLA ₂ mass was a region harboring PLA2G7, the gene that encodes lipoprotein-associated phospholipase A2.

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Most cited references 43

Record: found
Abstract: found
Article: not found

Newly identified loci that influence lipid concentrations and risk of coronary artery disease.

Cristen J Willer, Serena Sanna, Anne U. Jackson … (2008)

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

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Record: found
Abstract: found
Article: not found

Ensembl 2009

T. J. P. Hubbard, B. L. Aken, S. Ayling … (2009)

The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases, and other information for chordate, selected model organism and disease vector genomes. As of release 51 (November 2008), Ensembl fully supports 45 species, and three additional species have preliminary support. New species in the past year include orangutan and six additional low coverage mammalian genomes. Major additions and improvements to Ensembl since our previous report include a major redesign of our website; generation of multiple genome alignments and ancestral sequences using the new Enredo-Pecan-Ortheus pipeline and development of our software infrastructure, particularly to support the Ensembl Genomes project (http://www.ensemblgenomes.org/).

0 comments Cited 366 times – based on 0 reviews      Review now

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Record: found
Abstract: found
Article: not found

Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.

Lars Bertram, Christoph Lange, Kristina Mullin … (2008)

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Genet

Journal ID (publisher-id): plos

Journal ID (pmc): plosgen

Title: PLoS Genetics

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1553-7390

ISSN (Electronic): 1553-7404

Publication date Collection: April 2010

Publication date (Print): April 2010

Publication date (Electronic): 29 April 2010

Volume: 6

Issue: 4

Electronic Location Identifier: e1000928

Affiliations

[1 ]Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, United States of America

[2 ]Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, United States of America

[3 ]Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina, United States of America

[4 ]Scalable Computing Support Center, Duke University Medical Center, Durham, North Carolina, United States of America

[5 ]Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, United States of America

[6 ]Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, United States of America

University of Oxford, United Kingdom

Author notes

* E-mail: jeanette.mccarthy@ 123456duke.edu

Conceived and designed the experiments: SS DR. Analyzed the data: SS AMB. Contributed reagents/materials/analysis tools: TM XG. Wrote the paper: SS JRG JR GSG JJM.

Article

Publisher ID: 09-PLGE-RA-2139R3

DOI: 10.1371/journal.pgen.1000928

PMC ID: 2861686

PubMed ID: 20442857

SO-VID: 9ab86bba-a427-4e21-a47f-e9c2e3a6a606

Copyright © Suchindran et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 3 December 2009

Date accepted : 29 March 2010

Page count

Pages: 11

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