Contribution of genetic variation to pharmacokinetic variability and toxicity in

描述(申请人提供)：2010年，全球估计有880万结核病病例，其中230万例在非洲报告，110万例在艾滋病毒阴性的结核病病例中死亡，另有35万人在艾滋病毒阳性者中死亡。在结核病发病机制中，结核病病原体、宿主和药物暴露之间的复杂关系还知之甚少。世卫组织目前为新的药物敏感结核病病例推荐的治疗方案非常有效，艾滋病毒阴性患者的治愈率约为90%。然而，即使所有新的结核病病例都得到治疗，患者坚持接受治疗，仍有10%的患者(即全球88万名患者，非洲23万名患者)对治疗没有反应。即使坚持治疗，也有一定比例的利福平敏感型结核病患者对药物反应迟缓或无反应。在艾滋病毒感染患者中，这个问题甚至更加复杂和严重，因为目前的治疗方法似乎效率较低。还有其他患者可以成功治疗，但会出现毒性，从而导致治疗中断。虽然已认识到对药物治疗的可变反应的几个潜在决定因素(例如性别、年龄、种族)，但对抗结核治疗的反应的大部分变异性 毒品问题仍未得到解释。近年来，对药物代谢和治疗疗效个体间差异背后的遗传学的了解有了迅速的发展。药物遗传学领域包括在治疗效果和药物不良反应的背景下，研究与药物转运体、药物代谢酶和药物靶点相关的基因的异质性。很少有人进行研究来探索结核病的这一领域。通过这项研究，我们旨在探索和确定宿主遗传因素对结核病患者的药代动力学(即药物浓度)和动态(即治疗结果)变异性的影响。RAFAgene“研究是一个为期4年的项目，将嵌套在撒哈拉以南非洲进行的两个多国随机第三阶段结核病治疗试验中，即OFLOTUB和RAFA试验(注册号为NCT00216385和PACTR 201105000291300)。在这两项试验中登记参加药代动力学研究的患者将被抽样进行遗传分析(全基因组和有针对性的SNPs筛选，并在体外确认药代动力学和遗传特征之间的关联的生物学合理性)。拟议的项目由国家结核病和肺部医院(NHTPD)的Dissou Affolabi博士领导，合作伙伴包括塞内加尔的国家结核病项目、几内亚的Ignace Deen大学、开普敦大学(SA)、南非德班医学研究委员会、英国利物浦大学和英国伦敦卫生与热带医学院。

DESCRIPTION (provided by applicant): In 2010 there were an estimated 8.8 million incident cases of tuberculosis (TB) globally, with 2.3 million of these reported in Africa, 1.1 million deats among HIV-negative cases of TB and an additional 0.35 million deaths among people who were HIV-positive. The complex relationship between TB pathogen, host, and drug exposure in the pathogenesis of TB is poorly understood. The treatment regimen that is currently recommended by WHO for new cases of drug-susceptible TB is highly efficacious, with cure rates of around 90% in HIV-negative patients. However, even if all new TB cases were treated and patients were adherent to the treatment, there would still be 10% of patients (i.e. 880,000 patients worldwide, 230,000 patients in Africa) who fail to respond to treatment. Even if adherent to treatment, a proportion of patients, with rifampicin sensitive TB, are slow to respond to medication or are non-responders. The problem is even more complex and serious in HIV infected patients where the efficacy of the current treatments appears to be lower. Still other patients can be treated successfully, but will experience toxicity and thus treatment interruptions. While several potential determinants of the variable response to drug treatment are recognized (e.g. sex, age, ethnicity), much of the variability in response to anti-tuberculosis drugs remains unexplained. In recent years there has been a rapid development in the understanding of the genetics underlying inter- individual differences in drug metabolism and treatment efficacy. The field of pharmacogenetics encompasses the study of the heterogeneity in genes related to drug transporters, drug metabolizing enzymes and drug targets, in the context of efficacy of treatment and adverse drug reactions. Few studies have been conducted to explore this field for TB disease. Through this study we aim to explore and determine host genetic factors contributing to pharmacokinetic (i.e. drug concentration) and dynamic (i.e. treatment outcome) variability in TB patients. The "RAFAgene" study is a 4 year project which will be nested within two multi-country randomized phase III tuberculosis treatment trials, the OFLOTUB and RAFA trials (reg numbers NCT00216385 and PACTR 201105000291300) conducted in Sub-Saharan Africa. Patients enrolled in the pharmacokinetic studies within these 2 trials will be sampled for genetic analysis (genome-wide and targeted SNPs screening with in vitro confirmation of the biological plausibility of the association between pharmacokinetic and genetic characteristics). The proposed project is led by Dr. Dissou Affolabi at the National Hospital for TB and Pulmonary (NHTPD) with partners from the National TB program in Senegal, the University Ignace Deen in Guinea, the University of Cape Town (SA), the Medical Research Council in Durban (South Africa), the University of Liverpool UK and the London School of Hygiene and Tropical Medicine UK.