Molecular Genetics and Pathology Unit, Hospital of Divino Espirito Santo of Ponta Delgada, São Miguel Island, Azores, Portugal.
Mol Diagn Ther. 2009;13(4):261-8. doi: 10.2165/11317170-000000000-00000.
Glucuronidation reactions, catalyzed by uridine-diphosphate glucuronosyltransferase (UGT) enzymes, constitute a detoxification process that adds glucuronic acid to endogenous and exogenous compounds, aiding their excretion. UGT1A proteins have been implicated as risk factors for both the development of cancer and adverse drug effects.
Here, we assess the genome of 469 individuals from São Miguel Island (Azores, Portugal) in order to determine the frequencies of polymorphisms and haplotypes in UGT1A1, UGT1A6, and UGT1A7, the co-occurrence of reduced enzyme activity UGT1A variants related to irinotecan toxicity, and to calculate the extent of linkage disequilibrium (LD) in the genomic region encompassing these genes.
Allelic analysis disclosed the presence of rare alleles - UGT1A136 and UGT1A137--only found in individuals of African descent, and UGT1A74. These alleles confirm our previous results on the São Miguel Island genetic background. We identified five different genotypes in UGT1A1 and UGT1A6 and nine in UGT1A7. Haplotype analysis showed that three haplotypes constituted approximately 80% of the allelic variants. Interestingly, haplotype 3 (UGT1A128-UGT1A62-UGT1A73), with a frequency of 0.235, gathers the three alleles encoding the low-function UGT isoforms. Additionally, LD indicates a strong interaction between functional polymorphisms related to the alteration of the UGT enzyme activity.
In summary, the results demonstrate a high variability of alleles and haplotypes, which have important roles in modifying expression and activity of UGTs. The data presented here could improve the understanding of the predisposition to cancers and susceptibility to the adverse effects of irinotecan in the São Miguel Island population.
葡糖醛酸基转移酶（UGT）酶催化的葡糖醛酸化反应是一种解毒过程，它将葡糖醛酸添加到内源性和外源性化合物中，帮助它们排泄。UGT1A 蛋白已被认为是癌症发展和药物不良反应的风险因素。
在这里，我们评估了来自圣米格尔岛（葡萄牙亚速尔群岛）的 469 个人的基因组，以确定 UGT1A1、UGT1A6 和 UGT1A7 中的多态性和单倍型的频率、与伊立替康毒性相关的酶活性降低的 UGT1A 变体的共同发生，以及计算包含这些基因的基因组区域的连锁不平衡（LD）程度。
等位基因分析揭示了仅在非洲裔个体中存在的罕见等位基因 UGT1A136 和 UGT1A137--以及 UGT1A74。这些等位基因证实了我们之前关于圣米格尔岛遗传背景的结果。我们在 UGT1A1 和 UGT1A6 中鉴定了五种不同的基因型，在 UGT1A7 中鉴定了九种。单倍型分析表明，三个单倍型构成了大约 80%的等位基因变体。有趣的是，单倍型 3（UGT1A128-UGT1A62-UGT1A73），频率为 0.235，汇集了编码低功能 UGT 同工酶的三个等位基因。此外，LD 表明与 UGT 酶活性改变相关的功能多态性之间存在强烈的相互作用。
总之，结果表明等位基因和单倍型具有高度的变异性，这些变异性在调节 UGT 的表达和活性方面起着重要作用。这里呈现的数据可以提高对圣米格尔岛人群中癌症易感性和伊立替康不良反应易感性的理解。
