Single-Nucleotide Polymorphisms in LPA Explain Most of the Ancestry-Specific Variation in Lp(a) Levels in African Americans
Open Access
- 24 January 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (1), e14581
- https://doi.org/10.1371/journal.pone.0014581
Abstract
Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6×10−22, 27% change in Lp(a) per allele, ∼5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study.Keywords
This publication has 40 references indexed in Scilit:
- From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locusNature, 2010
- Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines GenePLoS Genetics, 2009
- Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart StudyPLoS Genetics, 2009
- Admixture Mapping of White Cell Count: Genetic Locus Responsible for Lower White Blood Cell Count in the Health ABC and Jackson Heart StudiesAmerican Journal of Human Genetics, 2008
- Admixture Mapping of an Allele Affecting Interleukin 6 Soluble Receptor and Interleukin 6 LevelsAmerican Journal of Human Genetics, 2007
- Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European AmericansJournal of Medical Genetics, 2006
- Efficiency and power in genetic association studiesNature Genetics, 2005
- Human protein reference database as a discovery resource for proteomicsNucleic Acids Research, 2004
- Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key?Gene, 1999
- The Apo(a) Gene is the Major Determinant of Variation in Plasma Lp(a) Levels in African AmericansAmerican Journal of Human Genetics, 1997