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

Deo RC, Wilson JG, Xing C, Lawson K, Kao WH, Reich D, Tandon A, Akylbekova E, Patterson N, Mosley TH, Boerwinkle E, Taylor HA - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America. rdeo@partners.org

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.

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Affected-Only Statistic at Equally Spaced Points across the genome for the Lp(a) Admixture Scan.The 95% credible interval for the peak at 6q25.3 includes the LPA and LPA2 genes.
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pone-0014581-g001: Affected-Only Statistic at Equally Spaced Points across the genome for the Lp(a) Admixture Scan.The 95% credible interval for the peak at 6q25.3 includes the LPA and LPA2 genes.

Mentions: Admixture mapping of Lp(a) reveals a compelling association of increased African ancestry with Lp(a) case status (upper quintile) at chromosome 6q25.3 (LOD 13.6, Figure 1). This far exceeds our threshold of significance of 5 for LOD scores [17] and suggests a marked association of local ancestry at this locus with Lp(a) level. In this region, individuals having Lp(a) levels in the upper quintile had a mean African ancestry of 87.4%, compared to 72.7% for those having Lp(a) values in the lower quintile (p<2×10−16). The 95% credible interval for this peak spans from 158 to 162 megabasepairs (Mb) and includes the LPA gene.


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

Deo RC, Wilson JG, Xing C, Lawson K, Kao WH, Reich D, Tandon A, Akylbekova E, Patterson N, Mosley TH, Boerwinkle E, Taylor HA - PLoS ONE (2011)

Affected-Only Statistic at Equally Spaced Points across the genome for the Lp(a) Admixture Scan.The 95% credible interval for the peak at 6q25.3 includes the LPA and LPA2 genes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3025914&req=5

pone-0014581-g001: Affected-Only Statistic at Equally Spaced Points across the genome for the Lp(a) Admixture Scan.The 95% credible interval for the peak at 6q25.3 includes the LPA and LPA2 genes.
Mentions: Admixture mapping of Lp(a) reveals a compelling association of increased African ancestry with Lp(a) case status (upper quintile) at chromosome 6q25.3 (LOD 13.6, Figure 1). This far exceeds our threshold of significance of 5 for LOD scores [17] and suggests a marked association of local ancestry at this locus with Lp(a) level. In this region, individuals having Lp(a) levels in the upper quintile had a mean African ancestry of 87.4%, compared to 72.7% for those having Lp(a) values in the lower quintile (p<2×10−16). The 95% credible interval for this peak spans from 158 to 162 megabasepairs (Mb) and includes the LPA gene.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America. rdeo@partners.org

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.

Show MeSH
Related in: MedlinePlus