UDP-Glucuronosyltransferase 1A1 Gene Polymorphisms and Total Bilirubin Levels in an Ethnically Diverse Cohort of Women Andrew L. Hong, Dezheng Huo, Hee-Jin Kim, Qun Niu, Donna L. Fackenthal, Shelly A. Cummings, Esther M. John, Dee W. West, Alice S. Whittemore, Soma Das, and Olufunmilayo I. Olopade Department of Medicine, Section of Hematology/Oncology (A.L.H., H.-J.K., Q.N., S.A.C., O.I.O.), Department of Health Studies (D.H.), and Department of Human Genetics (D.L.F., S.D., O.I.O.), University of Chicago, Chicago, Illinois, Northern California Cancer Center, Fremont, California (E.M.J., D.W.W.); and Stanford University School of Medicine, Stanford, California (D.W.W., A.S.W.) Received January 3, 2007; accepted April 30, 2007 ABSTRACT: The objective of this study was to investigate variations in UGT1A1 polymorphisms and haplotypes among African-American and Cau- casian 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 ac- counted for 71.8% of chromosomes, whereas five common haplo- types accounted for only 46.6% of chromosomes in African Amer- icans. 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 (R 2  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 correla- tion 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 pharmaco- genetic studies for adverse drug reactions in populations of Afri- can ancestry. The UDP-glucuronosyltransferase (UGT) 1A1 gene has been im- plicated in a number of processes, including conjugation of bilirubin from hemoglobin and hemoprotein turnover, detoxification of poten- tial carcinogens, phase II drug metabolism, and estradiol metabolism (Senafi et al., 1994; Bosma et al., 1995; Malfatti et al., 2005). The nine UGT1A isoforms are expressed to varying degrees in the liver (Strass- burg et al., 1997) and mammary tissue (Senafi et al., 1994; Chouinard et al., 2006). The number of TA repeats in the TATA promoter region of UGT1A1 has been shown to be inversely associated with the transcriptional activity of UGT1A1, with five and six repeats (allele *36 and *1, respectively) associated with high UGT1A1 activity and seven and eight repeats (alleles *28 and *37, respectively) associated with low UGT1A1 activity (Beutler et al., 1998). The genotype, (TA) 7 /(TA) 7 , has been associated with Gilbert’s syndrome, which presents with mild hyperbilirubinemia (Bosma et al., 1995). The unifying premise of integrative epidemiology suggested by Spitz et al. (2005) is that the same genes that are implicated in cancer risk may also be involved in a person’s propensity to carcinogenic exposure and/or to modulation of therapeutic outcome. Therefore, constructing genetic profiles that could be used to individualize ther- apy may also increase our understanding of cancer risk genes and may be applied to cancer development and prediction of outcome. To this end, differences in TA repeats of UGT1A1 have been shown to be responsible for the toxic effects of irinotecan, an anticancer drug (Iyer et al., 2002), and have also been linked with cancer susceptibility (Guillemette et al., 2000; Adegoke et al., 2004). Of interest are studies suggesting an association of UGT1A1 TA repeat polymorphisms with breast cancer among African Americans but not Caucasians (Guil- lemette et al., 2000, 2001). 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. Govern- ment or the Breast CFR. A.L.H., D.H., and H.-J.K. contributed equally to this work. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.106.014183. ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; PBREM, phenobarbital-responsive enhancer module; SNP, single nucleotide polymor- phism; LD, linkage disequilibrium; tSNP, tagging SNP; MAF, minor allele frequency; SBE, single base extension; HWE, Hardy-Weinberg equilibrium; ANOVA, analysis of variance. 0090-9556/07/3508-1254–1261$20.00 DRUG METABOLISM AND DISPOSITION Vol. 35, No. 8 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 14183/3226837 DMD 35:1254–1261, 2007 Printed in U.S.A. 1254 at ASPET Journals on June 21, 2017 dmd.aspetjournals.org Downloaded from