UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations

Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified. Mutations in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats, alter bi lirubin conjugation. Two missense mutations on one allele of UGT1A6 (UGT1A6 *2) result in T181A and R184S amino acid substitutions and reduced activity against phenolics, such as 4-nitrophenol, 4-hydroxycoumarin and butylated hydroxy anisole. We determined the frequency of these polymorphisms in 245 healthy men and women, aged 20-40 years and examined the relationship betwe en TA repeat number and serum bilirubin concentrations in a subset of 24 As ians and 169 Caucasians. The frequencies of the UGT1A1*28 genotypes were 0. 537, 0.348, 0.098, 0.008 and 0.008 for promoter TA repeats 6/6, 6/7, 7/7, 5 /6 and 6/8, respectively. Both allele and genotype frequencies varied by ra ce (P < 0.02), with 11% of the Caucasians and none of the Asians having the 7/7 genotype. Within both ethnic groups, serum bilirubin increased with in creased numbers of UGT1A1 promoter TA repeats (P = 0.0001). However, a stro ng ethnic group-by-UGT1A1 genotype interaction suggests that additional eth nic differences in bilirubin metabolism contribute to observed bilirubin co ncentrations. Genotype frequencies for UGT1A6*2 were 0.478, 0.392, 0.029, 0 .090, 0.012 for wild-type (wt)/wt, wt/T181A + R184S, wt/R184S, T181A + R184 S/T181A + R184S and T181A + R184S/R184S, respectively. The co-occurrence of polymorphisms in UGT1A1 and UGT1A6 differed from that expected (P < 0.0001 ): individuals homozygous wild-type for UGT1A1 and UGT1A6 were observed at twice the expected frequency; individuals homozygous variant for both genes were ten-fold more frequent and individuals homozygous wild-type for one g ene and homozygous variant for the other were ten-fold less frequent than e xpected. Overall, 8% were homozygous variant for both UGT1 polymorphisms an d 43% had at least one variant allele for both UGT1A1*28 and UGT1A6*2. Thes e highly prevalent polymorphisms, which result in modified expression and a ctivity of UGTs, may influence susceptibility to cancers associated with al tered metabolism of endogenous and xenobiotic compounds. Pharmacogenetics 9 :341-349 (C) 1999 Lippincott Williams & Wilkins.