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UGT1A1 is a major locus influencing bilirubin levels in African Americans.

Chen G, Ramos E, Adeyemo A, Shriner D, Zhou J, Doumatey AP, Huang H, Erdos MR, Gerry NP, Herbert A, Bentley AR, Xu H, Charles BA, Christman MF, Rotimi CN - Eur. J. Hum. Genet. (2011)

Bottom Line: We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes.None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829.Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r(2)≥0.74) with rs10929302.

View Article: PubMed Central - PubMed

Affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. chengu@mail.nih.gov

ABSTRACT
Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10(-8). The lowest P-value was 1.7 × 10(-22) for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10(-11); this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r(2)≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations.

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Related in: MedlinePlus

Corrected P-values and LD in this sample of African Americans (HUFS) for rs4236644 located in the promoter region of the SEMA3C gene. The red arrow points to the position of SNP rs4236644 in Europeans. The two red dots are for SNPs rs1358503 and rs10251660 that locally replicated the original discovery SNP (rs4236644) in individuals of European ancestry. SNPs rs1358503 and rs10251660 are in moderate LD (r2=0.33) with rs4236644 in Europeans.
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fig2: Corrected P-values and LD in this sample of African Americans (HUFS) for rs4236644 located in the promoter region of the SEMA3C gene. The red arrow points to the position of SNP rs4236644 in Europeans. The two red dots are for SNPs rs1358503 and rs10251660 that locally replicated the original discovery SNP (rs4236644) in individuals of European ancestry. SNPs rs1358503 and rs10251660 are in moderate LD (r2=0.33) with rs4236644 in Europeans.

Mentions: In addition, we replicated reported association between variants in the semaphorin 3C (SEMA3C) gene and bilirubin levels.16 The discovery SNP (rs4236644) located in the SEMA3C gene was locally replicated by two LD based SNPs (rs1358503 and rs10251680, P-values 0.0461 and 0.0447, respectively, Figure 2). Each SNP explained ∼1% of the variance in serum bilirubin levels in this study of African Americans.


UGT1A1 is a major locus influencing bilirubin levels in African Americans.

Chen G, Ramos E, Adeyemo A, Shriner D, Zhou J, Doumatey AP, Huang H, Erdos MR, Gerry NP, Herbert A, Bentley AR, Xu H, Charles BA, Christman MF, Rotimi CN - Eur. J. Hum. Genet. (2011)

Corrected P-values and LD in this sample of African Americans (HUFS) for rs4236644 located in the promoter region of the SEMA3C gene. The red arrow points to the position of SNP rs4236644 in Europeans. The two red dots are for SNPs rs1358503 and rs10251660 that locally replicated the original discovery SNP (rs4236644) in individuals of European ancestry. SNPs rs1358503 and rs10251660 are in moderate LD (r2=0.33) with rs4236644 in Europeans.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306855&req=5

fig2: Corrected P-values and LD in this sample of African Americans (HUFS) for rs4236644 located in the promoter region of the SEMA3C gene. The red arrow points to the position of SNP rs4236644 in Europeans. The two red dots are for SNPs rs1358503 and rs10251660 that locally replicated the original discovery SNP (rs4236644) in individuals of European ancestry. SNPs rs1358503 and rs10251660 are in moderate LD (r2=0.33) with rs4236644 in Europeans.
Mentions: In addition, we replicated reported association between variants in the semaphorin 3C (SEMA3C) gene and bilirubin levels.16 The discovery SNP (rs4236644) located in the SEMA3C gene was locally replicated by two LD based SNPs (rs1358503 and rs10251680, P-values 0.0461 and 0.0447, respectively, Figure 2). Each SNP explained ∼1% of the variance in serum bilirubin levels in this study of African Americans.

Bottom Line: We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes.None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829.Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r(2)≥0.74) with rs10929302.

View Article: PubMed Central - PubMed

Affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. chengu@mail.nih.gov

ABSTRACT
Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10(-8). The lowest P-value was 1.7 × 10(-22) for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10(-11); this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r(2)≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations.

Show MeSH
Related in: MedlinePlus