HEPATITIS C CLEARANCE AND HOST GENETIC FACTORS

描述：(申请人摘要) 应聘者即将完成为期三年的传染病奖学金，并已 在过去的两年里致力于研究人类白细胞之间的联系 在一项多队列研究中，乙肝病毒的抗原复合体的结果。穿过 此次拨款，候选人将在流行病学研究中使用分子遗传学工具 并因此将弥合流行病学家和基本医生之间的差距 科学家努力了解传染性非典型肺炎的免疫致病机制 疾病。从长远来看，这位候选人希望成为一名教职员工 对了解传染病结果感兴趣的成员 由基因决定的宿主反应的可变性。尤其是在 短期内，这位候选人对研究宿主遗传因素感兴趣 影响丙型肝炎转归以阐明丙型肝炎病毒机制 发病机制，这最终可能具有治疗和疫苗方面的意义。 这项工作将在大卫·托马斯博士的指导下进行，他已经 在丙型肝炎和流行病学方面的专业知识。与David博士合作 建立活着队列的流行病学家弗拉霍夫和玛丽博士 卡林顿是遗传学领域的领军人物，候选人将拥有 成功完成此任务所需的协作资源 项目。候选人将通过参加每周两个小时的学习来补充她的研究 传染病和肝炎相关会议周，每周出席 丙型肝炎研究会议，在感染性疾病中看病人 疾病/肝炎诊所，每周半天。她还计划参加一些课程 在流行病学、遗传学和病毒学方面。 全球超过1.7亿人感染丙型肝炎病毒(丙型肝炎病毒) 他们中有%的人持续感染，其余的人清除了病毒。 这种不同的结果差异不能用病毒或 环境因素。正如在其他慢性病毒感染中所显示的那样，它 很可能是由基因编程宿主因素决定的 这些结果。在过去，这些主机与病毒的交互一直很困难 由于对丙型肝炎病毒生物学知识的有限和分子水平的缺乏而进行探索 探索人类基因组的工具。然而，丙型肝炎病毒的生物学正在展开， 分子生物学的最新进展使人类基因组的检测成为可能 大范围的可变性。利用活着的注射吸毒者队列， 候选人将研究已清除病毒的131人和262人 与持续性丙型肝炎病毒感染的对照组相匹配。她将测试多态在 人类白细胞抗原等位基因和可能的致病基因 等位基因频率在清除和持续感染之间的扭曲 个人。在可能的情况下，将检查等位基因频率 哈代-温伯格均衡扭曲。卡方分析与单变量AND 进行多因素条件Logistic回归分析。这个 还将评估与丙型肝炎病毒基因型有关的相关性。成功就是 预计由于队列特征良好，分子工具存在， 事实证明，这种合作在乙肝研究中是富有成效的。

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.