Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations
Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations
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DOI：
10.1111/j.1469-1809.2010.00638.x
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发表时间：
2011-03-01
影响因子：
1.9
通讯作者：
Swallow, Dallas M.
中科院分区：
文献类型：
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作者：
Horsfall, Laura J.;Zeitlyn, David;Swallow, Dallas M.
P>覆盖UGT1A1（UDP-葡萄糖醛酸基转移酶1A1）TATA盒的短（TA）（n）重复序列（rs8175347）的变异与高胆红素血症（吉尔伯特综合征）和药物不良反应相关，并用于伊立替康的剂量建议。一些报告表明，低活性（风险）等位基因（(TA)(7) 和 (TA)(8))）在非洲人中非常常见，但与 UGT1A 基因复合体中可能调节这些反应的其他变体的关联模式尚不清楚。在来自欧洲和非洲的 2616 名受试者中检测了 rs8175347 和另外两种临床相关的 UGT1A 变体（rs11692021 和 rs10929302）。低活性 (TA)(n) 等位基因频率在赤道非洲最高，(TA)(7,) 在喀麦隆、加纳、苏丹南部和埃塞俄比亚阿努阿克最常见。单倍型多样性在赤道非洲也是最大的，但在埃塞俄比亚，不同种族群体的单倍型多样性差异很大。对样本子集的启动子进行重测序未发现新的变异，但对 rs34547608 和 rs887829 进行了分型并显示与 (TA)(n) 紧密相关。我们的结果表明，需要研究除 (TA)(n) 之外的 UGT1A 变体对伊立替康毒性以及溶血性贫血或人类免疫缺陷病毒蛋白酶抑制剂引起的高胆红素血症风险的影响，以便提供适当的药物遗传学建议。
P>Variation of a short (TA)(n) repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)(7) and (TA)(8))) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)(n) alleles frequencies were highest in equatorial Africa, (TA)(7,) being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)(n). Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)(n) on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.