Gilbert's syndrome and hyperbilirubinemia in protease inhibitor therapy - An extended haplotype of genetic variants increases risk in indinavir treatment
Gilbert's syndrome and hyperbilirubinemia in protease inhibitor therapy - An extended haplotype of genetic variants increases risk in indinavir treatment
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DOI：
10.1016/j.jhep.2008.12.030
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发表时间：
2009-05-01
影响因子：
25.7
通讯作者：
Strassburg, Christian P.
中科院分区：
文献类型：
--
作者：
Lankisch, Tim O.;Behrens, Georg;Strassburg, Christian P.
背景/目的：吉尔伯特综合征是一种常见的与药物不良反应相关的基因结合异常。遗传性UDP葡萄糖醛酸基转移酶(UGT)1A基因变异会影响基因的转录、诱导性和葡萄糖醛酸化活性。用于人类免疫缺陷病毒(HIV)感染和慢性病毒性肝炎的蛋白酶抑制剂可以抑制UGT。方法：采用Taqman 5‘核酸酶分析方法，对125例HIV感染者和42 7例健康献血员进行了UGT1A1*28、UGT1A3-66T/C、UGT1A7-57T/G、UGT1A7-57T/G、UGT1A7(N129K/R131K)等位基因分型，发现高胆红素血症发生率为42%。UGT1A1*28频率在HIV患者和对照组之间没有差异，但在高胆红素血症患者中显著高于对照组。UGT1A4标记单倍型纯合子携带者的频率随着高胆红素血症的增加而增加。结论：在IDV治疗中，除Gilbert综合征(UGT1A1*28)外，严重高胆红素血症的风险还与UGT1A3和UGT1A7基因变异有关。这种单倍型是预测蛋白水解酶抑制剂引起的副作用的有用指标。(C)2009年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background/Aims: Gilbert's syndrome is a frequent genetic conjugation abnormality associated with adverse drug effects. Genetic UDP glucuronosyltransferase (UGT)1A gene variants can influence gene transcription, inducibility and glucuronidation activity. Protease inhibitors used in human immunodeficiency virus (HIV) infection and chronic viral hepatitis can inhibit UGTs. Indinavir (IDV) can lead to hyperbilirubinemia in Gilbert's syndrome (UGT1A1*28), which does not explain interindividual severity differences and may thus involve additional UGT1A variants.Methods: One hundred and twenty-five HIV patients receiving IDV and 427 healthy blood donors were genotyped for the presence of UGT1A*28, UGT1A3-66T/C, UGT1A7 -57T/G, UGT1A7(N129K/R131K) USING Taqman 5' nuclease assays.Results: Hyperbilirubinemia was observed in 42%. UGT1A1*28 frequencies did not differ between HIV patients and controls but were significantly higher in hyperbilirubinemic patients. The frequency of homozygous carriers of the 4 UGT1A marker haplotype increased with hyperbilirubinemia affecting all patients with bilirubin levels >85 pmol/l.Conclusions: In IDV treatment the risk of severe hyperbilirubinemia is associated with genetic variants of the UGT1A3 and UGT1A7 genes in addition to Gilbert's syndrome (UGT1A1*28). This haplotype is a useful predictor of protease inhibitor-induced side effects. (c) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.