Universidade do Estado do Amazonas.
Fundação de Hematologia e Hemoterapia do Amazonas, Manaus.
Pharmacogenet Genomics. 2020 Oct;30(8):184-189. doi: 10.1097/FPC.0000000000000411.
Reduced function alleles in the TPMT and NUDT15 genes are risk factors for thiopurine toxicity. This study evaluated the influence of Native ancestry on the distribution of TPMT (rs1142345, rs1800460 and rs1800462) and NUDT15 (rs116855232) polymorphisms and compound metabolic phenotypes in 128 healthy males from the Brazilian Amazon. The average proportion of Native and European ancestry differed greatly and significantly between self-declared Amerindians and non-Amerindians, although extensive admixture in both groups was evident. Native ancestry was not significantly associated with the frequency distribution of the TPMT or NUDT15 polymorphisms investigated. The apparent discrepancy with our previous results for NUDT15 rs116855232 in the Ad Mixed American superpopulation of the 1000 Genomes Project is ascribed to the diversity of the Native populations of the Americas. Based on the inferred TPMT/NUDT15 compound metabolic phenotypes, the Clinical Pharmacogenetics Implementation Consortium recommendations for starting thiopurine therapy with reduced doses or to consider dose reduction applied respectively to 3-5% and to 12-20% of the study cohorts.
TPMT 和 NUDT15 基因的功能降低等位基因是硫嘌呤毒性的风险因素。本研究评估了土著血统对 TPMT（rs1142345、rs1800460 和 rs1800462）和 NUDT15（rs116855232）多态性以及 128 名来自巴西亚马逊的健康男性的复合代谢表型分布的影响。自我认定的美洲原住民和非美洲原住民之间的土著和欧洲血统的平均比例差异很大且显著，尽管两组之间存在广泛的混合。土著血统与所研究的 TPMT 或 NUDT15 多态性的频率分布无显著相关性。与我们之前在 1000 基因组计划的 Ad 混合美洲超级人群中对 NUDT15 rs116855232 的结果明显不一致，这归因于美洲土著人群的多样性。基于推断的 TPMT/NUDT15 复合代谢表型，临床药物基因组学实施联盟建议对 3-5%和 12-20%的研究队列开始使用低剂量硫嘌呤治疗或考虑减少剂量。
