title: UGT1A1 is a major locus influencing bilirubin levels in African Americans.
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.
authors.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
authors.forename: Guanjie
authors.initials: G
authors.lastname: Chen
authors.forename: Edward
authors.initials: E
authors.lastname: Ramos
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Daniel
authors.initials: D
authors.lastname: Shriner
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Ayo P
authors.initials: AP
authors.lastname: Doumatey
authors.forename: Hanxia
authors.initials: H
authors.lastname: Huang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Norman P
authors.initials: NP
authors.lastname: Gerry
authors.forename: Alan
authors.initials: A
authors.lastname: Herbert
authors.forename: Amy R
authors.initials: AR
authors.lastname: Bentley
authors.forename: Huichun
authors.initials: H
authors.lastname: Xu
authors.forename: Bashira A
authors.initials: BA
authors.lastname: Charles
authors.forename: Michael F
authors.initials: MF
authors.lastname: Christman
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
mesh_terms: D000328:Adult; D001741:Black or African American; D001663:Bilirubin / Q000097:blood* / Q000235:genetics; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme
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