Amorim Gustavo, Jaworski James, 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
medRxiv. 2023 Sep 1:2023.08.30.23294860. doi: 10.1101/2023.08.30.23294860.
Genetic polymorphisms have been associated with risk of anti-tuberculosis 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 2015-2019, and who were evaluable 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 anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.
Among 903 participants in multivariable genetic association analyses, 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 rapid acetylators, but not statistically significant at the 5% level. A polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms in 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 , and the genes and , but none achieved genome-wide significance.
In a clinical cohort representing three regions of Brazil, acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.
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/复发的相关性进行了特征分析。
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年间开始治疗且可进行药物遗传学评估的痰培养确诊的药物敏感型肺结核患者。治疗包括2个月的异烟肼、利福平或利福布汀、吡嗪酰胺和乙胺丁醇，然后是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。分析包括与抗结核药物肝毒性或药代动力学相关的20个基因中的43个多态性。对一个毒性病例对照亚组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，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有关，包括肝毒性。快速乙酰化者治疗失败/复发的可能性更大，但在5%水平上无统计学意义。一种多态性（rs412543）与包括肝毒性在内的治疗相关不良事件风险增加有关。多态性与治疗相关肝毒性以及治疗失败/复发风险增加有关。[此处原文缺失相关基因信息]中的多态性与不良事件风险降低以及失败/复发风险增加有关。在全外显子组测序中，肝毒性与[此处原文缺失相关基因信息]中的一种多态性以及[此处原文缺失相关基因信息]和[此处原文缺失相关基因信息]基因有关，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，乙酰化状态与治疗相关不良事件风险有关。其他显著的多态性值得在更大的研究人群中进行研究。
