Genomics of Primary Biliary Cirrhosis

描述(申请人提供)：原发性胆汁性肝硬变(PBC)的遗传和非遗传危险因素尚未得到很好的研究。因此，这种慢性淤胆性肝病的病因和发病机制尚不清楚，PBC继续降低这种疾病的主要患者--许多女性的生活质量和预期寿命。为了开始破译这种复杂的自身免疫性疾病的遗传易感性和环境风险，我们创建了梅奥诊所PBC遗传流行病学(MCPGE)登记和生物谱系资料库。这项研究资源目前包括410名PBC患者和290名临床对照，他们在年龄(+2.5岁)、性别、种族和居住状态方面进行了单独匹配。PBC的遗传易感性的概念已经确立并被广泛接受。最近，一种PBC小鼠模型(NOD.C3C4)被用于鉴定自身免疫性胆道疾病1(Abd1)基因。尽管取得了进展，但对PBC的遗传易感性、其非遗传风险因素以及它们相互作用导致疾病的方式仍有待仔细调查。在这个应用中，我们想通过利用MCPGE研究资源的500个病例和500个对照来检验人类免疫体(即编码免疫系统基本组件的已知基因的总和)的遗传变异(即单核苷酸多态-SNPs)和与小鼠Abd1基因座同源的人类基因与PBC相关的假设。这项建议的具体目的是：目的1我们将使用定制的847个免疫基因(10,734个SNP)的SNP阵列对病例和对照进行分型并进行遗传关联分析；目标2我们将使用与小鼠Abd1基因座同源的250个人类基因(4,337个SNP)定制的SNP阵列对病例和对照进行分型并进行遗传关联分析；目标3我们将：(A)验证已提出的PBC的危险因素(如吸烟、尿路感染、激素替代治疗)，并评估新的可能的危险因素(如二手烟、水源、农药暴露)；以及(B)在目标1和目标2中测试环境暴露和被发现与PBC风险相关的遗传变异之间的相互作用。这项研究将具有重大的翻译影响，因为它将确定与PBC相关的基因多态和非遗传风险因素。通过剖析与PBC进一步研究相关的遗传和环境风险，这项调查将成为未来风险评估和疾病预防战略的基础，以及探索牵连机制的基础研究，并可能导致这种毁灭性疾病的新疗法。 公共卫生相关性：这项翻译研究旨在检查人类对原发性胆汁性肝炎(PBC)的易感性，PBC是一种慢性自身免疫性肝病，会降低生活质量，缩短预期寿命。使用我们最近开发的Mayo Clinic PBC遗传流行病学(MCPGE)注册表和Biospecimen Repository，我们建议进行研究，以确定导致PBC的遗传变异和非遗传(即环境)风险因素。如果成功，这项研究将为改善这种毁灭性疾病的预防和创新疗法铺平道路。

DESCRIPTION (provided by applicant): The genetic and non-genetic risk factors for primary biliary cirrhosis (PBC) have not yet been well investigated. As a result, the cause and pathogenesis of this chronic cholestatic liver disease remain unclear, and PBC continues to diminish the quality of life and decrease the life expectancy of many women, the main sufferers of this disease. In an effort to begin deciphering the genetic susceptibility and environmental risks of this complex autoimmune disease, we created the Mayo Clinic PBC Genetic Epidemiology (MCPGE) registry and biospecimen repository. This research resource currently comprises 410 PBC patients and 290 clinic-based controls individually matched for age (+2.5 years), sex, race, and state of residence. The concept of genetic predisposition to PBC is well established and widely accepted. Recently, a mouse model of PBC (NOD.c3c4) was used to identify an autoimmune biliary disease 1 (Abd1) locus. Despite progress, the genetic susceptibility to PBC, its non-genetic risk factors, as well as the way in which they interact to result in disease, await meticulous investigation. In this application, we would like to test the hypothesis that genetic variants (i.e. single nucleotide polymorphisms - SNPs) of the human immunome (i.e. the sum of known genes that encode the essential components of the immune system) and human genes homologous to the murine Abd1 locus are associated with PBC, by utilizing 500 cases and 500 controls of the MCPGE research resource. The Specific Aims of this proposal are: Aim 1 we will genotype the cases and controls using a custom SNP array of 847 immune genes (10,734 SNPs) and perform genetic association analyses; Aim 2 we will genotype the cases and controls with a custom SNP array of 250 human genes homologous to murine Abd1 locus (4,337 SNPs) and perform genetic association analyses; Aim 3 we will: (a) verify proposed risk factors of PBC (i.e. smoking, urinary tract infection, hormone replacement therapy) and assess novel putative risk factors (i.e. second hand smoking, water source, pesticides exposure); and (b) test for interaction between environmental exposure and genetic variants found to be associated with PBC risk in Aims 1 and 2. This study will have significant translational impact because it will identify genetic polymorphisms and nongenetic risk factors associated with PBC. By dissecting the genetic and environmental risks that are relevant for further study in PBC, this investigation will become the foundation for future risk assessment and disease prevention strategies as well as for basic research studies exploring implicated mechanisms and potentially leading to novel treatments for this devastating disease. Public Health Relevance: This translational study seeks to examine the susceptibility of humans to Primary Biliary Cirrhosis (PBC), a chronic autoimmune liver disease that diminishes quality of life and shortens life expectancy. Using our recently developed Mayo Clinic PBC Genetic Epidemiology (MCPGE) Registry and Biospecimen Repository, we propose studies to identify genetic variants and nongenetic (i.e. environmental) risk factors that contribute to PBC. If successful, this study will pave the road to improved prevention and innovative therapies for this devastating disease.