Comprehensive Analysis of Genomic Variation in the LPA Locus and Its Relationship to Plasma Lipoprotein(a) in South Asians, Chinese, and European Caucasians
- 1 February 2010
- journal article
- research article
- Published by Wolters Kluwer Health in Circulation: Cardiovascular Genetics
- Vol. 3 (1), 39-46
- https://doi.org/10.1161/circgenetics.109.907642
Abstract
Functional copy number variation in the apolipoprotein(a) gene (LPA) underlies a variable number of protein kringle domains repeated in tandem in the lipoprotein(a) [Lp(a)] particle. Genomic analysis of LPA, including both single-nucleotide polymorphisms (SNPs) and kringle IV type 2 (KIV-2) copy number, has yet to be performed. First, we genotyped 49 SNPs within 100 kb of LPA in a multiethnic sample comprising South Asians (n=330), Chinese (n=304), and European Caucasians (n=272). Second, using quantitative polymerase chain reaction, we estimated the KIV-2 copy number in each sample. European Caucasians had the lowest KIV-2 copy number but displayed the strongest correlation between KIV-2 copy number and plasma Lp(a) concentration (r(s)=-0.31, P=4.2 x 10(-7)). SNP rs10455872, only prevalent in European Caucasians, was strongly associated with both plasma Lp(a) concentration (P=4.2 x 10(-29)) and KIV-2 copy number (P=7.2 x 10(-5)). LPA SNP rs6415084, within the same haplotype block as the KIV-2 variation, was significantly associated with both Lp(a) concentration and KIV-2 copy number in the same direction in all 3 ethnicities [Lp(a), P=5.3 x 10(-7); KIV-2, P=2.6 x 10(-4)]. SNPs and KIV-2 copy number together explain a larger proportion of variation in plasma Lp(a) concentrations in European Caucasians (36%) than in Chinese (27%) or South Asians (21%). LPA SNPs are in linkage disequilibrium with KIV-2 copy number, but KIV-2 copy number explains an increment in plasma Lp(a) variation over SNPs alone. Thus, both SNPs and KIV-2 copy number should be included in future genetic epidemiology studies of Lp(a).Keywords
This publication has 30 references indexed in Scilit:
- Replication of genetic associations with plasma lipoprotein traits in a multiethnic sampleJournal of Lipid Research, 2009
- Mendelian RandomizationJAMA, 2009
- Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6qJournal of Lipid Research, 2009
- Determination of lipoprotein(a) kringle repeat number from genomic DNA: copy number variation genotyping using qPCRJournal of Lipid Research, 2009
- Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association StudiesPLOS ONE, 2008
- Analysis of 17,576 Potentially Functional SNPs in Three Case–Control Studies of Myocardial InfarctionPLOS ONE, 2008
- LPA and PLG Sequence Variation and Kringle IV-2 Copy Number in Two PopulationsHuman Heredity, 2008
- Association of Gene Variants With Incident Myocardial Infarction in the Cardiovascular Health StudyArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- Principal components analysis corrects for stratification in genome-wide association studiesNature Genetics, 2006