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

TitleSingle-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans.
Publication TypeJournal Article
Year of Publication2011
AuthorsDeo RC, Wilson JG, Xing C, Lawson K, Kao LWH, Reich D, Tandon A, Akylbekova E, Patterson N, Mosley TH, Boerwinkle E, Taylor HA
JournalPLoS One
Volume6
Issue1
Paginatione14581
Date Published2011 Jan 24
ISSN1932-6203
KeywordsAfrican Americans, African Continental Ancestry Group, Cardiovascular Diseases, European Continental Ancestry Group, Genetic Loci, Genetic Markers, Humans, Kringles, Lipoprotein(a), Polymorphism, Single Nucleotide
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.

DOI10.1371/journal.pone.0014581
Alternate JournalPLoS One
PubMed ID21283670
PubMed Central IDPMC3025914
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
K08 HL098361 / HL / NHLBI NIH HHS / United States
HL092550 / HL / NHLBI NIH HHS / United States
K01 DK067207 / DK / NIDDK NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
HL082896 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
K08 HL098361-02 / HL / NHLBI NIH HHS / United States
K08 HL098361-01A1 / HL / NHLBI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
K01DK067207 / DK / NIDDK NIH HHS / United States
RL1 HL092550 / HL / NHLBI NIH HHS / United States
N01HC95170 / HL / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
R01 HL084107 / HL / NHLBI NIH HHS / United States
R21 DK073482 / DK / NIDDK NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
UL1RR024982 / RR / NCRR NIH HHS / United States
UL1 RR024982 / RR / NCRR NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
N01-HC-95171 / HC / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01-HC-95172 / HC / NHLBI NIH HHS / United States
N01HC95171 / HL / NHLBI NIH HHS / United States
R01 HL082896 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
N01-HC-95170 / HC / NHLBI NIH HHS / United States
N01HC95172 / HL / NHLBI NIH HHS / United States