Amorim Gustavo, Jaworski James, Yang Jing, Cordeiro-Santos Marcelo, Kritski Afrânio L, Figueiredo Marina C, Turner Megan, Andrade Bruno B, Velez Edwards Digna R, Santos Adalberto R, Rolla Valeria C, Sterling Timothy R, Haas David W
Vanderbilt University Medical Center, Department of Biostatistics.
Vanderbilt University Medical Center, Department of Medicine, Division of Epidemiology.
Pharmacogenet Genomics. 2025 Feb 1;35(2):55-64. doi: 10.1097/FPC.0000000000000552. Epub 2024 Oct 15.
Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.
Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.
Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A , and the genes METTL17 and PRSS57 , but none achieved genome-wide significance.
In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence.
基因多态性与抗结核治疗毒性风险相关。我们对巴西接受结核病治疗的成年人中不良事件以及治疗失败/复发的相关因素进行了特征分析。
在巴西结核病区域前瞻性观察研究（RePORT）中对参与者进行随访。我们纳入了2015年至2019年间开始治疗且符合药物遗传学条件的经培养确诊的药物敏感型肺结核患者。治疗方案包括2个月的异烟肼、利福平或利福布汀、吡嗪酰胺和乙胺丁醇，随后4个月的异烟肼和利福平或利福布汀，并进行24个月的随访。分析包括20个与抗结核药物肝毒性或药代动力学相关基因中的43个多态性。在一个病例对照毒性亚组中进行了全外显子组测序。
在903名参与多变量基因关联分析的参与者中，NAT2慢乙酰化状态与2级或更高级别的治疗相关不良事件风险增加相关，包括肝毒性。NAT2快乙酰化者治疗失败/复发的可能性更高，但在5%水平上无统计学意义。一种谷胱甘肽S-转移酶M1（GSTM1）多态性（rs412543）与治疗相关不良事件风险增加相关，包括肝毒性。有机阴离子转运多肽1B1（SLCO1B1）多态性与治疗相关肝毒性以及治疗失败/复发风险增加相关。核受体亚家族1/2（NR1/2）中的多态性与不良事件风险降低以及失败/复发风险增加相关。在全外显子组测序中，肝毒性与VTI1A基因以及甲基转移酶样17（METTL17）和丝氨酸蛋白酶57（PRSS57）基因中的多态性相关，但均未达到全基因组显著性。
在代表巴西三个地区的临床队列中，NAT2乙酰化状态与治疗相关不良事件风险相关。其他显著的多态性值得在更大的研究人群中进行研究，特别是关于治疗失败/复发风险。
