Abstract
The objective of this study was to investigate variations in UGT1A1 polymorphisms and haplotypes among African-American and Caucasian women and to assess whether variants other than UGT1A1*28 are associated with total serum bilirubin levels. The (TA)n repeats and 14 single nucleotide polymorphisms (SNPs) in the UGT1A1 gene were genotyped in 335 African Americans and 181 Caucasians. Total serum bilirubin levels were available in a subset of 125 women. Allele frequencies of all SNPs and (TA)n repeats were significantly different between African Americans and Caucasians. In Caucasians, three common haplotypes accounted for 71.8% of chromosomes, whereas five common haplotypes accounted for only 46.6% of chromosomes in African Americans. Mean total serum bilirubin levels were significantly lower (p = 0.005) in African Americans (0.36 mg/dl) than in Caucasians (0.44 mg/dl). The (TA)n repeats explained a significant amount of variation in total bilirubin levels (R2 = 0.27, p < 0.0001), whereas other SNPs were less correlative. Thus, significant variations in UGT1A1 haplotype structure exist between African Americans and Caucasians in this relatively large cohort of women. The correlation of UGT1A1 with total bilirubin levels was mainly due to (TA)n repeats in Caucasians but a clear correlation was not observed in African Americans because of the high diversity of haplotypes and the small sample size. These data have implications for the design of epidemiologic studies of cancer susceptibility and pharmacogenetic studies for adverse drug reactions in populations of African ancestry.
Footnotes
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This work was supported by National Cancer Institute Grant CA-R01 89085-01A, the Falk Medical Research Trust, and the National Cancer Institute, National Institutes of Health, under Request for Application CA-95-003 as part of the Breast Cancer Family Registries (CFR), and through cooperative agreements with the Northern California Cancer Center. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of collaborating centers in the Breast CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the Breast CFR.
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A.L.H., D.H., and H.-J.K. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.014183.
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ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; PBREM, phenobarbital-responsive enhancer module; SNP, single nucleotide polymorphism; LD, linkage disequilibrium; tSNP, tagging SNP; MAF, minor allele frequency; SBE, single base extension; HWE, Hardy-Weinberg equilibrium; ANOVA, analysis of variance.
- Received January 3, 2007.
- Accepted April 30, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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