Host Genetic Contribution to HCV Outcomes

描述（由研究者提供）：干扰素和利巴韦林联合治疗丙型肝炎病毒（HCV）的一个持续发现是，根据病毒基因型，40% - 70%的人对治疗有持续的病毒学反应，10- 20%的人会有初步反应，需要重新治疗，25- 35%的人根本没有反应。病毒基因型、病毒突变、与其他病毒合并感染、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，对治疗反应的部分差异可能是由宿主基因的差异来解释的。由于干扰素（IFN） 1和2是HCV感染的有效治疗方法，激活和被这些细胞因子激活的基因可能对成功的治疗很重要。目前还没有研究系统地检查构成I型IFN反应途径的基因变异，并将其与治疗反应联系起来。在克利夫兰接受HCV治疗的大多数患者在4所大学附属医院的专科诊所就诊。在该项目中，2000-2011年期间在这些诊所接受治疗的hiv阴性患者将对IFN1通路关键基因的单核苷酸多态性（snp）进行基因分型。在估计的6000名患者中，我们预计将招募1200名既往治疗过的患者和1000名预期患者。然后将等位基因和单倍型频率在持续或无病毒学反应的患者之间进行比较，以确定相关基因。虽然有数百个基因被IFN1诱导或抑制，但在这项初步研究中，我们选择了80-100个已知的基因，这些基因是病毒感知、IFN1产生、信号传导或效应机制以及反应调节的关键。根据LD、已知的或潜在的功能作用、等位基因频率以及在基因分型分析中的表现，已经在每个基因中鉴定出大约10-20个SNP标记。环境因素的值将从入组访谈和患者图表中获得。标准和新开发的方法将用于单位点和单倍型分析。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，并包括标记，将允许分析祖先作为一个连续变量。预计这项工作将允许更好的预处理分层，并将确定导致不良反应的遗传因素。该项目将通过DNA标记检查丙型肝炎病毒感染治疗反应不良的潜在遗传基础。对治疗有反应的人的基因差异将与对治疗无反应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.