Single-nucleotide polymorphisms in LPA explain most of the Ancestry-specific variation in Lp(a) levels in African Americans

Rahul C. Deo, James G. Wilson, Chao Xing, Kim Lawson, W. H. Linda Kao, David Reich, Arti Tandon, Ermeg Akylbekova, Nick Patterson, Thomas H. Mosley, Eric Boerwinkle, Herman A. Taylor

Research output: Contribution to journalArticle

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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 frequencydifferentiated 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.

Original languageEnglish (US)
Article numbere14581
JournalPLoS One
Volume6
Issue number1
DOIs
StatePublished - 2011

Fingerprint

Lipoprotein(a)
African Americans
Polymorphism
lipoproteins
single nucleotide polymorphism
Single Nucleotide Polymorphism
ancestry
Nucleotides
heart
Genes
Genome
Kringles
Population
loci
genome
myocardial infarction
heart diseases
atherosclerosis
Coronary Disease
Heart Diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Single-nucleotide polymorphisms in LPA explain most of the Ancestry-specific variation in Lp(a) levels in African Americans. / Deo, Rahul C.; Wilson, James G.; Xing, Chao; Lawson, Kim; Linda Kao, W. H.; Reich, David; Tandon, Arti; Akylbekova, Ermeg; Patterson, Nick; Mosley, Thomas H.; Boerwinkle, Eric; Taylor, Herman A.

In: PLoS One, Vol. 6, No. 1, e14581, 2011.

Research output: Contribution to journalArticle

Deo, RC, Wilson, JG, Xing, C, Lawson, K, Linda Kao, WH, Reich, D, Tandon, A, Akylbekova, E, Patterson, N, Mosley, TH, Boerwinkle, E & Taylor, HA 2011, 'Single-nucleotide polymorphisms in LPA explain most of the Ancestry-specific variation in Lp(a) levels in African Americans', PLoS One, vol. 6, no. 1, e14581. https://doi.org/10.1371/journal.pone.0014581
Deo, Rahul C. ; Wilson, James G. ; Xing, Chao ; Lawson, Kim ; Linda Kao, W. H. ; Reich, David ; Tandon, Arti ; Akylbekova, Ermeg ; Patterson, Nick ; Mosley, Thomas H. ; Boerwinkle, Eric ; Taylor, Herman A. / Single-nucleotide polymorphisms in LPA explain most of the Ancestry-specific variation in Lp(a) levels in African Americans. In: PLoS One. 2011 ; Vol. 6, No. 1.
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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 frequencydifferentiated 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.",
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AU - Reich, David

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AU - Taylor, Herman A.

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