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

https://doi.org/10.1016/S1079-9796(03)00071-8Get rights and content

Abstract

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.

Introduction

There is a strong body of evidence that the mild elevation of unconjugated bilirubin that is characteristic of Gilbert’s syndrome is related to a polymorphism of the UDP glucuronosyltransferase 1 (UGT1A1) gene [1], [2]. The promoter region contains a run of thymine-adenine (TA) repeats; usually there are six (TA)6. The extended repeat sequence, (TA)7, has been found in otherwise normal persons with the slightly elevated bilirubin levels typical of Gilbert’s syndrome, although it is clear that other polymorphisms of UGT1A1 can underlie this condition [2]. Furthermore, unusually high bilirubin levels have been observed in individuals with this genotype with conditions which are associated with increased red-cell turnover, including heterozygosity for β-thalassemia [3], [4], β-thalassemia intermedia [5], neonatal jaundice associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency in some populations [6], hereditary spherocytosis [7], congenital dyserythropoietic anemia type II [8], and sickle cell anemia [9].

We have previously reported an unexpectedly high frequency of the (TA)7 allele in the population of Sri Lanka [10]. In patients with Hb E-β-thalassemia, this allele was associated with unusually high levels of bilirubin and a significantly increased frequency of gallstones and gall bladder disease. Because Hb E-β-thalassemia occurs at a high frequency in Asian populations, and because of the potential role of polymorphisms in the UGT1A1 promoter in generating this important complication, we have carried out a population survey of the frequency of the different numbers of (TA) repeats in a wide range of ethnic groups. Our findings suggest that there is considerable diversity in the frequency of the (7)/(7) genotype, an observation which, as well as its practical implications, raises questions about the mechanism for the diversity of minisatellite regions of DNA of this type among different populations.

Section snippets

Subjects

Blood samples were obtained from 1617 subjects from the ethnic groups listed in Table 1. In addition, 35 DNA samples were obtained from chimpanzees. Ethical approval for this study was obtained as part of the programme for population studies of thalassemia and its complications by the Central Oxford Research Ethics Committee, the Oxford Tropical Research Ethics Committee, and the Ethics Committees of the countries that were involved.

DNA analysis

DNA was prepared from small frozen whole-blood samples by a

Results

The results of this survey are summarized in Table 1. There was a remarkably wide diversity in the frequency of the (TA7) (TA7) genotype, with the highest values observed in populations of the Indian subcontinent, notably India, Sri Lanka, and Bangladesh. The frequency was much lower in the Chinese populations of Hong Kong and in Thailand and Indonesia and it was only rarely found in the island populations of Papua New Guinea, Tonga, and Fiji. It varied considerably among the different European

Discussion

This study has revealed a wide variation in the frequency of number of (TA) repeats in the promoter of the UGT1A1 gene. Hitherto, there have been very little published data on this topic. Studies of small groups of individuals of European, Asian, and African ethnic backgrounds showed that the frequency of the (TA)7 allele was lower in Asians (in this case mainly Chinese) than in Europeans and also reported a wider diversity of repeat numbers among individuals from North and Central America with

Acknowledgements

This work was supported by The Wellcome Trust, MRC, a Commonwealth Scholarship (A.P.), and the Leverhulme Trust. We thank Ros Harding and Eden Haverfield for helpful discussion and Liz Rose for typing the manuscript.

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