Genomics of Primary Biliary Cirrhosis

描述（由申请人提供）：原发性胆汁性肝硬化（PBC）的遗传和非遗传危险因素尚未得到很好的研究。因此，这种慢性胆汁淤积性肝病的病因和发病机制仍不清楚，PBC继续降低许多妇女的生活质量，降低这种疾病的主要患者的预期寿命。为了开始破译这种复杂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）登记处和生物标本库。该研究资源目前包括410名PBC患者和290名临床对照，分别匹配年龄（≥2.5岁）、性别、种族和居住州。PBC的遗传易感性的概念已经建立并被广泛接受。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）位点。尽管取得了进展，但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研究。在这个应用程序中，我们希望通过利用500例病例和500例MCPGE研究资源的对照，测试人类免疫组（即编码免疫系统基本成分的已知基因的总和）的遗传变异（即单核苷酸多态性- snp）和与小鼠Abd1位点同源的人类基因与PBC相关的假设。本提案的具体目标是：目标1，我们将使用847个免疫基因（10,734个SNP）的定制SNP阵列对病例和对照组进行基因分型，并进行遗传关联分析；目的2：我们将用250个与小鼠Abd1位点同源的人类基因（4337个SNP）的定制SNP阵列对病例和对照组进行基因分型，并进行遗传关联分析；目标3我们将：(a)验证PBC的风险因素（如吸烟、尿路感染、激素替代疗法），并评估新的假定风险因素（如二手烟、水源、农药暴露）；(b)测试环境暴露与目标1和目标2中发现的与PBC风险相关的遗传变异之间的相互作用。这项研究将具有重要的转化影响，因为它将确定与PBC相关的遗传多态性和非遗传风险因素。通过剖析与PBC进一步研究相关的遗传和环境风险，该调查将成为未来风险评估和疾病预防策略的基础，以及探索相关机制的基础研究，并可能导致这种毁灭性疾病的新治疗方法。

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.