RACIAL VARIABILITY IN THE UDP-GLUCURONOSYLTRANSFERASE-1 (UGT1A1) PROMOTER - A BALANCED POLYMORPHISM FOR REGULATION OF BILIRUBIN METABOLISM

A polymorphism in the promoter of the UDP-glucuronosyltransferase 1 (U GT1A1) gene has been shown to cause Gilbert syndrome, a benign form of unconjugated bilirubinemia. Promoters containing seven thymine adenin e (ta) repeats have been found to be less active than the wild-type si x repeats, and the serum bilirubin levels of persons homozygous or eve n heterozygous for seven repeats have been found to be higher than tho se with the wild-type six repeats. We have now examined the genotypes in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there is a strong correlation between promo ter repeat number and bilirubin level, between ethnic groups we found that this relationship to be inverse. Among people of African ancestry there are, in addition to those with six and seven repeats, also pers ons who have five or eight repeats. Using a reporter gene we show that there is an inverse relationship between the number of ta repeats and the activity of the promoter through the range of 5-8 ta repeats, An incidental finding was a polymorphism at nucleotide -106, tightly link ed to the (ta)(5) haplotype, Serum bilirubin levels are influenced by many factors, both genetic and environmental. We suggest that the unst able UGT1A1 polymorphism may serve to ''fine-tune'' the plasma bilirub in level within population groups, maintaining it at a high enough lev el to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants.