The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications

The promoter region of the UDP glucuronosyltransferase 1 gene (UGT1A1) contains a run of thymine-adenine (TA) repeats, usually six (TA)6. As well as its relationship to Gilbert’s syndrome, homozygosity for the extended sequence, (TA)7 (TA)7, has been found to be an important risk factor for hyperbilirubinemia and gallstones in patients with hemoglobin E-β-thalassemia and other intermediate forms of β thalassemia. To assess the importance of this polymorphism in these common disorders a wide-scale population study of the relative frequency of the size alleles of the UGT1A1 promoter has been carried out. Homozygosity for the (TA)7 allele occurs in 10–25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurs at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations show a much greater diversity of length alleles than other populations. These findings define those populations with a high frequency of hemoglobin E-β-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gall bladder disease and provide evolutionary insights into how these polymorphisms have arisen and are so unequally distributed among human populations.