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      Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart Study

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          Abstract

          Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase ( LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG ( p = 2.7×10 −6) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations.

          Author Summary

          Single-base changes in DNA can affect biochemical measures, such as blood cholesterol or lipid levels. Such changes or “variants” can be associated with a trait either because they cause the trait or because they are linked to other causal variants. In either case, the associated variant(s) may be useful in predicting the trait. The chromosomes in which DNA is packaged cross over and recombine with each other in each generation, so that in historically separate populations, such as Africans and Europeans, the patterns of genetic linkage between variants differ. In the current study, we analyzed a large group of African Americans, testing genetic variants that had been associated with cholesterol and lipid levels in European-derived populations to assess their predictive value on two different genetic backgrounds within the same cohort. The ability of some variants to predict cholesterol or lipid traits was strongly dependent on genetic background, indicating that they may be tightly linked to other causal variant(s) in European populations and may not, themselves, be directly responsible for trait variability. We conclude that the predictive value of specific variants for risk assessment can differ critically across populations.

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          Applied Logistic Regression

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            Genomewide association analysis of coronary artery disease.

            Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. Copyright 2007 Massachusetts Medical Society.
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              Newly identified loci that influence lipid concentrations and risk of coronary artery disease.

              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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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                January 2009
                January 2009
                16 January 2009
                : 5
                : 1
                : e1000342
                Affiliations
                [1 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ]Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                [3 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
                [4 ]Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
                [5 ]Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
                [6 ]Jackson State University, Jackson, Mississippi, United States of America
                [7 ]Tougaloo College, Tougaloo, Mississippi, United States of America
                [8 ]G. V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi, United States of America
                Queensland Institute of Medical Research, Australia
                Author notes

                Conceived and designed the experiments: RCD DR JGW. Performed the experiments: DR AW. Analyzed the data: RCD DR AT EA NP JGW. Contributed reagents/materials/analysis tools: DR NP DS HAT JGW. Wrote the paper: RCD DR HAT JGW. Provided guidance related to pre-publication findings: SK.

                Article
                08-PLGE-RA-0764R2
                10.1371/journal.pgen.1000342
                2613537
                19148283
                6b8f053f-5ec9-40c2-a2fb-fa5df012acbf
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 27 June 2008
                : 15 December 2008
                Page count
                Pages: 11
                Categories
                Research Article
                Cardiovascular Disorders/Coronary Artery Disease
                Genetics and Genomics

                Genetics
                Genetics

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