UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians:: relationships to serum bilirubin concentrations
UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians:: relationships to serum bilirubin concentrations
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DOI：
10.1097/00008571-199906000-00009
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发表时间：
1999-06-01
期刊：
影响因子：
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通讯作者：
Potter, JD
中科院分区：
文献类型：
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作者：
Lampe, JW;Bigler, J;Potter, JD
改变 UDP-葡萄糖醛酸基转移酶 (UGT) 活性的多态性已被鉴定。 UGT1A1 基因 (UGT1A1*28) 启动子发生突变，导致 5、7 或 8 个而不是 6 个胸腺嘧啶-腺嘌呤 (TA) 重复，从而改变胆红素结合。 UGT1A6 (UGT1A6*2) 一个等位基因上的两个错义突变导致 T181A 和 R184S 氨基酸取代，并降低对酚类物质（如 4-硝基苯酚、4-羟基香豆素和丁基羟基苯甲醚）的活性。我们确定了 245 名年龄 20-40 岁的健康男性和女性中这些多态性的频率，并检查了 24 名亚洲人和 169 名白种人的亚组中 TA 重复次数与血清胆红素浓度之间的关系。对于启动子TA重复6/6、6/7、7/7、5/6和6/8，UGT1A1*28基因型的频率分别为0.537、0.348、0.098、0.008和0.008。等位基因和基因型频率因种族而异（P < 0.02），其中 11% 的白种人具有 7/7 基因型，而没有亚洲人具有 7/7 基因型。在两个种族中，血清胆红素随着 UGT1A1 启动子 TA 重复次数的增加而增加 (P = 0.0001)。然而，UGT1A1 基因型与种族之间的强烈相互作用表明，胆红素代谢的额外种族差异有助于观察到的胆红素浓度。 UGT1A6*2 的基因型频率为 0.478、0.392、0.029、0.090、0.012（野生型（wt）/wt、wt/T181A + R184S、wt/R184S、T181A + R184S/T181A + R184S 和 T181A +）分别为 R184S/R184S。 UGT1A1 和 UGT1A6 多态性的共现与预期不同 (P < 0.0001)：观察到 UGT1A1 和 UGT1A6 纯合野生型个体的频率是预期频率的两倍；个体中两个基因的纯合变异的频率比预期高十倍，而个体中一个基因的纯合野生型和另一个基因的纯合变异的频率比预期低十倍。总体而言，8% 的 UGT1 多态性均为纯合变异，43% 的 UGT1A1*28 和 UGT1A6*2 至少有一个变异等位基因。这些高度普遍的多态性导致 UGT 的表达和活性改变，可能会影响与内源性和外源性化合物代谢改变相关的癌症易感性。药物遗传学 9：341-349 (C) 1999 Lippincott Williams & Wilkins。
Polymorphisms that alter UDP-glucuronosyltransferase (UGT) activities have been identified. Mutations in the promoter of the UGT1A1 gene (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats, alter bilirubin conjugation. Two missense mutations on one allele of UGT1A6 (UGT1A6*2) result in T181A and R184S amino acid substitutions and reduced activity against phenolics, such as 4-nitrophenol, 4-hydroxycoumarin and butylated hydroxy anisole. We determined the frequency of these polymorphisms in 245 healthy men and women, aged 20-40 years and examined the relationship between TA repeat number and serum bilirubin concentrations in a subset of 24 Asians and 169 Caucasians. The frequencies of the UGT1A1*28 genotypes were 0.537, 0.348, 0.098, 0.008 and 0.008 for promoter TA repeats 6/6, 6/7, 7/7, 5/6 and 6/8, respectively. Both allele and genotype frequencies varied by race (P < 0.02), with 11% of the Caucasians and none of the Asians having the 7/7 genotype. Within both ethnic groups, serum bilirubin increased with increased numbers of UGT1A1 promoter TA repeats (P = 0.0001). However, a strong ethnic group-by-UGT1A1 genotype interaction suggests that additional ethnic differences in bilirubin metabolism contribute to observed bilirubin concentrations. Genotype frequencies for UGT1A6*2 were 0.478, 0.392, 0.029, 0.090, 0.012 for wild-type (wt)/wt, wt/T181A + R184S, wt/R184S, T181A + R184S/T181A + R184S and T181A + R184S/R184S, respectively. The co-occurrence of polymorphisms in UGT1A1 and UGT1A6 differed from that expected (P < 0.0001): individuals homozygous wild-type for UGT1A1 and UGT1A6 were observed at twice the expected frequency; individuals homozygous variant for both genes were ten-fold more frequent and individuals homozygous wild-type for one gene and homozygous variant for the other were ten-fold less frequent than expected. Overall, 8% were homozygous variant for both UGT1 polymorphisms and 43% had at least one variant allele for both UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms, which result in modified expression and activity of UGTs, may influence susceptibility to cancers associated with altered metabolism of endogenous and xenobiotic compounds. Pharmacogenetics 9:341-349 (C) 1999 Lippincott Williams & Wilkins.