Dataset Information

Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project.

ABSTRACT: BACKGROUND:Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. METHODOLOGY/PRINCIPAL FINDINGS:We tested a set of ?50,000 polymorphisms from ?2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. CONCLUSIONS/SIGNIFICANCE:We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

SUBMITTER: Musunuru K

PROVIDER: S-EPMC3357427 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project.

Musunuru Kiran K Romaine Simon P R SP Lettre Guillaume G Wilson James G JG Volcik Kelly A KA Tsai Michael Y MY Taylor Herman A HA Schreiner Pamela J PJ Rotter Jerome I JI Rich Stephen S SS Redline Susan S Psaty Bruce M BM Papanicolaou George J GJ Ordovas Jose M JM Liu Kiang K Krauss Ronald M RM Glazer Nicole L NL Gabriel Stacey B SB Fornage Myriam M Cupples L Adrienne LA Buxbaum Sarah G SG Boerwinkle Eric E Ballantyne Christie M CM Kathiresan Sekar S Rader Daniel J DJ

PloS one 20120521 5

<h4>Background</h4>Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.<h4>Methodology/principal findings</h4>We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density l ...[more]

PMID: 22629316

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Project description:ImportanceStroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.ObjectiveTo investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.Design, setting, and participantsThe National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.Main outcomes and measuresDiscovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).ResultsWe identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).Conclusions and relevanceExome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

Dataset Information

Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project.

Publications

Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project.

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