Beutler E, Gelbart T, Demina A
The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8170-4. doi: 10.1073/pnas.95.14.8170.
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.
尿苷二磷酸葡萄糖醛酸基转移酶1（UGT1A1）基因启动子的多态性已被证明会导致吉尔伯特综合征，这是一种非结合胆红素血症的良性形式。已发现含有七个胸腺嘧啶腺嘌呤（ta）重复序列的启动子活性低于野生型的六个重复序列，并且已发现七个重复序列的纯合子甚至杂合子个体的血清胆红素水平高于具有野生型六个重复序列的个体。我们现在研究了亚洲、非洲和高加索血统人群的基因型。虽然在高加索种族群体中，启动子重复序列数量与胆红素水平之间存在很强的相关性，但在不同种族群体之间，我们发现这种关系是相反的。在非洲血统的人群中，除了有六个和七个重复序列的个体外，还有五个或八个重复序列的个体。使用报告基因，我们发现在5 - 8个ta重复序列范围内，ta重复序列的数量与启动子活性之间存在反比关系。一个偶然的发现是在核苷酸 -106处存在多态性，它与（ta）5单倍型紧密连锁。血清胆红素水平受遗传和环境等多种因素影响。我们认为，不稳定的UGT1A1多态性可能有助于在人群组内“微调”血浆胆红素水平，将其维持在足够高的水平以提供抗氧化损伤的保护，但又保持在足够低的水平以防止婴儿发生核黄疸。
