Host Genetic Contribution to HCV Outcomes

描述(由研究人员提供)：干扰素和利巴韦林联合治疗丙型肝炎病毒(丙型肝炎病毒)的一个持续发现是，40-70%的人将对治疗产生持续的病毒学反应，具体取决于病毒的基因型，10-20%的人将出现初步反应并需要再次治疗，而25-35%的人将完全没有反应。病毒基因型、病毒突变、与其他病毒的混合感染、年龄、性别、肥胖、肝毒素和种族等因素都会影响治疗结果。然而，治疗反应的部分变异性可能是由宿主遗传学的差异解释的。由于干扰素(干扰素)1和2已被证实是治疗丙型肝炎病毒感染的方法，激活和被这些细胞因子激活的基因对于成功的治疗很可能是重要的。目前还没有研究系统地检测构成I型干扰素反应途径的基因变异，并将其与治疗反应联系起来。在克利夫兰，大多数接受丙型肝炎病毒治疗的患者都在4所大学附属医院的专科诊所就诊。在该项目中，将对2000-2011年间在这些诊所接受治疗的艾滋病毒阴性患者进行IFN1途径关键基因的单核苷酸多态(SNPs)基因分型。在估计的6000名患者中，我们预计招募1200名既往治疗的患者和1000名前瞻性的患者。然后，将比较那些持续或没有病毒学反应的人的等位基因和单倍型频率，以确定相关基因。尽管IFN1诱导或抑制了数百个基因，但在这项初步研究中，我们选择了80-100个已知对病毒感知、IFN1的产生、信号或效应机制以及反应调节至关重要的基因。根据LD、已知或潜在的功能作用、等位基因频率和在基因分型分析中的表现，在每个基因上已经确定了大约10-20个SNP标记。环境因素的值将从登记面谈和患者图表中获得。标准和新开发的方法将用于单基因座和单倍型分析。分析将是多变量的，并考虑到潜在的基因-基因相互作用和影响反应的环境因素。此外，我们将控制人口分层，并包括允许将祖先作为连续变量进行分析的标记。预计这项工作将允许更好地进行治疗前分层，并将查明导致反应不佳的遗传因素。公共卫生相关性本项目将通过DNA标记手段，研究丙型肝炎病毒感染治疗反应差的潜在遗传基础。有反应的人的基因差异将与治疗无效的人的基因差异进行比较。

DESCRIPTION (provided by investigator): A constant finding in the combined interferon and ribavirin treatment of the hepatitis C virus (HCV) is that 40- 70 per cent will have a sustained virologic response to therapy, depending on the viral genotype, 10-20 per cent will have an initial response and require re-treatment, and 25-35 per cent will fail to respond at all. Viral genotype, viral mutation, co-infection with other viruses, age, sex, obesity, hepatotoxins and ethnicity, among other factors, influence treatment outcomes. Part of the variability in response to therapy, however, is likely explained by differences in host genetics. Since interferon (IFN) 1 and 2 are proven therapies for HCV infection, genes that activate and are activated by these cytokines are likely to be important for successful therapy. There have been no studies that systematically examined variations in the genes that make up the type I IFN response pathway and related this to therapeutic response. The majority of patients treated for HCV in Cleveland are seen at specialty clinics in the 4 University-affiliated hospitals. In this project, HIV-negative patients treated between 2000-2011 at these clinics will be genotyped for single nucleotide polymorphisms (SNPs) in key genes of the IFN1 pathway. Out of an estimated 6,000 patients, we anticipate enrolling 1,200 individuals with previous treatment and 1000 prospectively. Allele and haplotype frequencies will then be compared between those with sustained or no virologic response to identify the associated genes. Although hundreds of genes are induced or suppressed by IFN1, for this pilot study we have chosen 80-100 genes known to be key for viral sensing, production of IFN1, signaling or effector mechanisms and modulation of the response. Some 10-20 SNP markers have been identified in each gene based on LD, their known or potential functional role, their allele frequency and their performance in genotyping assays. Values for environmental factors will be obtained from the enrollment interview and patient's charts. Standard and newly developed approaches will be used for single locus and haplotype analyses. The analyses will be multivariable and take into account potential gene-gene interactions and environmental factors influencing the response. In addition, we will control for population stratification and include markers that will allow for analysis of ancestry as a continuous variable. It is expected that this work will permit better pre-treatment stratification and that it will identify genetic factors responsible for the poor responses. PUBLIC HEALTH RELEVANCE This project will examine the underlying genetic basis for poor responses to treatment for hepatitis C virus infection by means of DNA markers. Differences in the genes of people who do respond will be compared to differences in genes of people who do not respond to therapy.