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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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Mapping of Lp(a) associated SNP regions to transcription factor binding motifs.Sequences surrounding each of the 24 Lp(a) significantly associated SNPs were scanned for transcription factor binding motifs from the Transfac and Jaspar databases. Sequence logos for binding motifs predicted to be disrupted by allelic variation are displayed along with the HGNC symbol of associated transcription factor and the Jaspar or Transfac motif ID. Only transcription factors with literature evidence of liver expression are shown.
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pone-0014581-g005: Mapping of Lp(a) associated SNP regions to transcription factor binding motifs.Sequences surrounding each of the 24 Lp(a) significantly associated SNPs were scanned for transcription factor binding motifs from the Transfac and Jaspar databases. Sequence logos for binding motifs predicted to be disrupted by allelic variation are displayed along with the HGNC symbol of associated transcription factor and the Jaspar or Transfac motif ID. Only transcription factors with literature evidence of liver expression are shown.

Mentions: In addition to identifying SNPs that may contribute to disease risk, genetic association studies have the potential to illuminate the regulatory transcriptional architecture of quantitative traits. Recent studies have mapped transcription factor motifs to DNA sequences harboring genetic variants and have subsequently used chromatin immunoprecipitation to demonstrate genotype-dependent occupancy of the binding site [21]. To identify potential transcription factor binding sites that may be influenced by genetic variation at the Lp(a) locus, we scanned the genomic sequences surrounding the 24 Lp(a) associated SNPs using Jaspar (http://www.jaspar.genereg.net) and Transfac (http://www.gene-regulation.com) positional weight matrices (PWMs) with quantitative thresholds for match quality (see Methods). We focused on transcription factors with previously documented expression in liver (the site of Lp(a) production) and identified 7 SNPs for which genetic variation is likely to influence binding of such transcription factors (Figure 5). The transcription factors for the various SNPs include members of the GATA (rs3124787, rs6919346, rs6926458), and Forkhead families (rs2255830, rs2457550). Interestingly, the strongly associated rs6930542 SNP is expected to influence the binding of YY1, a ubiquitously expressed transcription factor with potential for either activating or repressive effects on gene expression [22]. In this case the C allele associated with higher Lp(a) levels and higher frequencies in African ancestral populations would be expected to disrupt YY1 binding, suggesting that the baseline transcriptional effect of YY1 at this site would be repressive. Further experiments in liver tissue and/or cell lines will be needed to validate these predictions.


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)

Mapping of Lp(a) associated SNP regions to transcription factor binding motifs.Sequences surrounding each of the 24 Lp(a) significantly associated SNPs were scanned for transcription factor binding motifs from the Transfac and Jaspar databases. Sequence logos for binding motifs predicted to be disrupted by allelic variation are displayed along with the HGNC symbol of associated transcription factor and the Jaspar or Transfac motif ID. Only transcription factors with literature evidence of liver expression are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0014581-g005: Mapping of Lp(a) associated SNP regions to transcription factor binding motifs.Sequences surrounding each of the 24 Lp(a) significantly associated SNPs were scanned for transcription factor binding motifs from the Transfac and Jaspar databases. Sequence logos for binding motifs predicted to be disrupted by allelic variation are displayed along with the HGNC symbol of associated transcription factor and the Jaspar or Transfac motif ID. Only transcription factors with literature evidence of liver expression are shown.
Mentions: In addition to identifying SNPs that may contribute to disease risk, genetic association studies have the potential to illuminate the regulatory transcriptional architecture of quantitative traits. Recent studies have mapped transcription factor motifs to DNA sequences harboring genetic variants and have subsequently used chromatin immunoprecipitation to demonstrate genotype-dependent occupancy of the binding site [21]. To identify potential transcription factor binding sites that may be influenced by genetic variation at the Lp(a) locus, we scanned the genomic sequences surrounding the 24 Lp(a) associated SNPs using Jaspar (http://www.jaspar.genereg.net) and Transfac (http://www.gene-regulation.com) positional weight matrices (PWMs) with quantitative thresholds for match quality (see Methods). We focused on transcription factors with previously documented expression in liver (the site of Lp(a) production) and identified 7 SNPs for which genetic variation is likely to influence binding of such transcription factors (Figure 5). The transcription factors for the various SNPs include members of the GATA (rs3124787, rs6919346, rs6926458), and Forkhead families (rs2255830, rs2457550). Interestingly, the strongly associated rs6930542 SNP is expected to influence the binding of YY1, a ubiquitously expressed transcription factor with potential for either activating or repressive effects on gene expression [22]. In this case the C allele associated with higher Lp(a) levels and higher frequencies in African ancestral populations would be expected to disrupt YY1 binding, suggesting that the baseline transcriptional effect of YY1 at this site would be repressive. Further experiments in liver tissue and/or cell lines will be needed to validate these predictions.

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