HEPATITIS C CLEARANCE AND HOST GENETIC FACTORS

描述：（申请人摘要） 该候选人正在完成为期三年的传染病奖学金， 在过去的两年里致力于研究人类白细胞 一项多队列研究中抗原复合物与B型肝炎病毒结局的关系通过 这项资助，候选人将使用分子遗传学工具在流行病学 从而弥合流行病学家和基础研究人员之间的差距。 科学家们努力了解感染性疾病的免疫病理机制， 疾病从长远来看，候选人希望成为一名教师 有兴趣了解传染病结果的成员， 宿主反应的遗传决定的变异性。特别是在 短期而言，该候选人对研究宿主遗传因素感兴趣， 影响丙型肝炎的结果，以阐明丙型肝炎病毒的机制 致病机制，这最终可能具有治疗和疫苗的意义。 这项工作将在大卫托马斯博士的指导下进行， 丙型肝炎和流行病学方面的专业知识。与大卫博士合作 Vlahov博士是建立ALIVE队列的流行病学家，玛丽博士 卡林顿，在遗传学领域的领导者，候选人将有 成功完成这项工作所需的协作资源 项目候选人将通过参加2小时的研究来补充她的研究。 传染病和肝炎相关会议周，每周参加一次 丙型肝炎研究会议，并看到病人在一个传染性 疾病/肝炎诊所，每周半天。她还计划参加课程 流行病学、遗传学和病毒学。 全世界有超过1.7亿人感染丙型肝炎病毒（HCV），85 他们中的10%有持续感染，其余的清除病毒。 这种异质性结果差异不能用病毒或 环境因素正如其他慢性病毒感染所显示的那样， 很可能是宿主因素，可能是基因编程决定的 这些结果。在过去，这些宿主与病毒的相互作用是困难的 由于对HCV生物学知识的有限和缺乏分子生物学知识， 探索人类基因组的工具。然而，HCV生物学正在展开， 分子生物学的最新进展允许检测人类基因组 大规模的变化。使用注射毒品使用者的ALIVE队列， 候选人将研究131名已清除病毒的人和262名 与持续HCV感染的对照组相匹配。她将测试多态性， 人类白细胞抗原等位基因和假定的致病基因 清除和持续感染之间等位基因频率的扭曲 个体在可能的情况下，将检查等位基因频率 Hardy-Weinberg平衡扭曲卡方分析和单变量和 将进行多变量条件logistic回归。的 还将评估与HCV基因型的相关性。成功是 由于该队列已得到充分表征，因此存在分子工具， 这种合作在HBV研究中被证明是富有成效的。

DESCRIPTION: (Applicant's Abstract) The candidate is completing a three year Infectious Diseases fellowship and has devoted the last two years to studying associations of the human leukocyte antigen complex to hepatitis B virus outcomes in a multi-cohort study. Through this grant, the candidate will use molecular genetics tools in an epidemiologic setting and will thus bridge the gap between the epidemiologists and basic scientists in an effort to understand immunopathogenic mechanisms of infectious diseases. Long-term, the candidate would like to establish herself as a faculty member interested in understanding infectious disease outcomes by examining the genetically-determined variability of the host response. In particular, in the short-term, this candidate is interested in studying host genetic factors that affect hepatitis C outcomes to elucidate mechanisms of hepatitis C virus pathogenesis, which eventually may have therapeutic and vaccine implications. The work will be performed under the guidance of Dr. David Thomas who has expertise in hepatitis C and epidemiology. In collaboration with Dr. David Vlahov, the epidemiologist who established the ALIVE cohort, and with Dr. Mary Carrington, a leader in the field of genetics, the candidate will have the collaborative resources necessary for the successful completion of this project. The candidate will complement her research by attending 2 hours per week of infectious diseases and hepatitis related conferences, attending weekly hepatitis C research meetings, and seeing patients in an infectious diseases/hepatitis clinic one half-day per week. She also plans to take courses in epidemiology, genetics, and virology. Over 170 million people worldwide are infected with hepatitis C virus (HCV), 85 percent of them have a persistent infection and the remainder clear the virus. This heterogeneous outcome difference is not explained by viral or environmental factors. As has been shown in other chronic viral infections, it is likely that host factors, which may be genetically programmed determine these outcomes. In the past, these host-virus interactions have been difficult to explore because of limited knowledge of HCV biology and lack of molecular tools to explore the human genome. However, HCV biology is unfolding and the recent advances in molecular biology permit detection of human genomic variability on a large scale. Using the ALIVE cohort of injection drug users, the candidate will study 131 individuals who have cleared the virus and 262 matched controls with persistent HCV infection. She will test polymorphisms in the human leukocyte antigen alleles and putative pathogenic genes for distortions in allele frequency between the clearance and persistently infected individuals. Where possible, the allele frequencies will be checked for Hardy-Weinberg equilibrium distortions. Chi-square analysis and univariate and multivariate conditional logistic regression will be performed. The associations will also be assessed with regards to HCV genotype. Success is anticipated since the cohort is well-characterized, the molecular tools exist, and the collaborations have proven to be productive in HBV studies.