Abstract
The UDP-glycosyltransferase (UGT1A) gene complex plays a critical role in the hepatic metabolism of a variety of chemicals, toxins, and drugs including bilirubin and acetaminophen. At least 13 different exon 1 sequences confer different binding specificities, while common exons 2–5 provide glycosyltransferase function. Mutations and polymorphisms within the UGT1A complex may help explain the phenotypic variability observed in drug metabolism. The frequency of three known polymorphisms in this complex: the UGT1A1 (TA)n promoter polymorphism (UGT1A1*28), and the UGT1A6 T181A and R184S mutations (UGT1A6*2), were determined in a cohort of Thai patients with HbE/beta-thalassemia (n=260) and African-American patients with sickle cell anemia (n=163), compared to published results for Caucasian persons (n=100). The UGT1A1 (TA)n promoter polymorphisms were identified by size discrimination using an ABI310® genetic analyzer, while the UGT1A6 mutations were identified using PCR amplification of the flanking sequence followed by restriction enzyme digestion at the polymorphic sites. The frequency of the abnormal UGT1A1 (TA)7 allele was lowest among Thai patients (0.15) and highest for African-American patients (0.48); Caucasians had an intermediate allelic frequency (0.29). The abnormal UGT1A1 7/7 genotype that confers the phenotype of Gilbert Syndrome was present in only 1.1% of Thai patients but was identified in 13.5% of African-American patients. Additional variant UGT1A1 alleles with 5 or 8 (TA) repeats were identified only in African-Americans. The frequency of both the T181A and R184S mutations within the UGT1A6 coding sequence ranged from 0.21 to 0.34, but were lower among both Thai and African-American patients than published values for Caucasians. Because these three genetic polymorphisms are known to be in linkage disequilibrium, the haplotype frequencies for the wildtype sequence (6/+/+) and the mutant sequence (7/−/−) were next estimated. Among African-Americans, the frequency of the 6/+/+ haplotype was 0.44, while the frequency of the 7/−/− was 0.14, totalling only 0.58 of the patients. Thai patients had a frequency of 0.73 for the 6/+/+ sequence and 0.09 for the 7/−/− sequence for a total of 0.82. Published values for Caucasians include a frequency of 0.66 for the 6/+/+ sequence and 0.28 for the 7/−/− sequence, for a total of 0.94. These data indicate that the UGT1A gene complex among Thai and African-American patients with hematological diseases has considerable variability compared to Caucasians. African-Americans have the highest frequency of variant UGT1A1 promoter polymorphisms and the lowest linkage disequilibrium, consistent with the older evolutionary timeframe in this population. Although Thai patients have a relatively low frequency of the abnormal UGT1A1 promoter allele and UGT1A6 mutations, they too have evidence of evolutionary drift. Taken together, these data suggest that common polymorphisms within the UGT1A gene complex may have important effects on the phenotypic variability observed in drug metabolism.
Allele and Haplotype Frequency of UGT1A Polymorphisms
Polymorphism Thai African-American Caucasian UGT1A1 (TA)5 .00 .07 .00 UGT1A1 (TA)6 .85 .48 .71 UGT1A1 (TA)7 .15 .37 .29 UGT1A1 (TA)8 .00 .07 .00 UGT1A6 T181A .21 .21 .32 UGT1A6 R184S .22 .26 .34 6/+/+ haplotype .73 .44 .65 7/−/− haplotype .09 .14 .29
Markers for Mapping by Admixture Linkage Disequilibrium in African American and Hispanic Populations
