Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter:: A balanced polymorphism for regulation of bilirubin metabolism?
Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter:: A balanced polymorphism for regulation of bilirubin metabolism?
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DOI：
10.1073/pnas.95.14.8170
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发表时间：
1998-07-07
影响因子：
11.1
通讯作者：
Demina, A
中科院分区：
文献类型：
--
作者：
Beutler, E;Gelbart, T;Demina, A
UDP-葡萄糖醛酸基转移酶1（UGT 1A 1）基因启动子的多态性已被证明可引起吉尔伯特综合征，一种良性的非结合型胆红素血症。已发现含有7个胸腺嘧啶腺嘌呤（ta）重复序列的启动子比野生型6个重复序列的活性低，并且已发现7个重复序列纯合甚至杂合的人的血清胆红素水平高于具有野生型6个重复序列的人。我们现在已经检查了亚洲人、非洲人和高加索人的基因型。虽然在高加索人种中，启动子重复序列数和胆红素水平之间存在很强的相关性，但在人种之间，我们发现这种关系是相反的。在非洲血统的人中，除了有六个和七个重复的人之外，还有五个或八个重复的人。利用报告基因，我们发现在5-8个重复序列的范围内，启动子的活性与重复序列的数目呈负相关。一个偶然的发现是与（ta）（5）单倍型紧密连锁的核苷酸-106的多态性。血清胆红素水平受遗传和环境等多种因素的影响。我们认为，不稳定的UGT 1A 1多态性可能有助于“微调”人群中的血浆胆红素水平，使其保持在足够高的水平，以提供对氧化损伤的保护，但在一个足够低的水平，以防止核黄疸婴儿。
A polymorphism in the promoter of the UDP-glucuronosyltransferase 1 (UGT1A1) gene has been shown to cause Gilbert syndrome, a benign form of unconjugated bilirubinemia. Promoters containing seven thymine adenine (ta) repeats have been found to be less active than the wild-type six repeats, and the serum bilirubin levels of persons homozygous or even heterozygous for seven repeats have been found to be higher than those 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 promoter 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 persons 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 linked to the (ta)(5) haplotype, Serum bilirubin levels are influenced by many factors, both genetic and environmental. We suggest that the unstable UGT1A1 polymorphism may serve to "fine-tune" the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants.