Genomics of Primary Biliary Cirrhosis

原发性胆汁性肝硬化的基因组学

• 批准号: 7609209
• 负责人: KONSTANTINOS N LAZARIDIS
• 金额: $ 30.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609209
• 关键词: Age; Animal Model; Antibodies; Antigens; Autoimmune Diseases; Autoimmune Process; Basic Science; Biliary; Blood specimen; Chronic; Clinic; Coin; Complex; Congenic Mice; Custom; DNA analysis; Data; Development; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Environmental Tobacco Smoke; Epidemiologic Studies; Epithelium; Etiology; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genomics; Genotype; Homologous Gene; Hormone replacement therapy; Human; Immune; Immune system; Individual; Inflammatory Response; Innovative Therapy; Investigation; Life Expectancy; Liver diseases; Mediating; Mitochondria; Mus; Pathogenesis; Patients; Predisposition; Prevention; Prevention strategy; Primary biliary cirrhosis; Process; Quality of life; Questionnaires; Race; Registries; Reporting; Resources; Risk; Risk Assessment; Risk Factors; Self Tolerance; Self-Administered; Serum; Single Nucleotide Polymorphism; Smoke; Smoking; Smoking History; Source; Sum; System; Testing; Urinary tract infection; Water; Woman; base; case control; disorder prevention; evidence base; genetic association; genetic epidemiology; genetic risk factor; genetic variant; improved; mouse model; non-genetic; novel; pesticide exposure; public health relevance; repository; research study; residence; sex; translational study

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.

描述（由申请人提供）：原发性胆汁肝硬化（PBC）的遗传和非遗传危险因素尚未得到充分研究。结果，这种慢性胆固性肝病的原因和发病机理尚不清楚，PBC继续降低生活质量并降低许多妇女的预期寿命，这是这种疾病的主要患者。为了开始解释这种复杂的自身免疫性疾病的遗传敏感性和环境风险，我们创建了Mayo Clinic PBC遗传流行病学（MCPGE）注册表和生物循环库。目前，该研究资源包括410名PBC患者和290个基于诊所的对照，分别匹配年龄（+2.5岁），性别，种族和居住状态。遗传易感性PBC的概念已得到充分确立并被广泛接受。最近，使用PBC的小鼠模型（NOD.C3C4）来识别自身免疫性胆道疾病1（ABD1）基因座。尽管进步，但对PBC的遗传敏感性，其非遗传危险因素以及它们相互作用而导致疾病的方式，等待细致的研究。在此应用中，我们想检验以下假设：人类免疫组的遗传变异（即单核苷酸多态性-SNP）（即，编码免疫系统基本组成部分的已知基因的总和）和与Murine ABD1基因座同源的人类基因相关的PBC与PBC相关的MCCAGE与MCTE的ROSTISS相关。该提案的具体目的是：目标1我们将使用847个免疫基因（10,734 SNP）的自定义SNP阵列进行基因型和对照，并进行遗传关联分析； AIM 2我们将使用250个与鼠ABD1基因座（4,337 SNP）同源的250个人类基因的自定义SNP阵列进行基因型和对照。目标3我们将：（a）验证PBC的拟议危险因素（即吸烟，尿路感染，激素替代疗法）并评估新颖的推定危险因素（即二手吸烟，水源，农药暴露）； （b）在目标1和2中发现与PBC风险相关的环境暴露与遗传变异之间的相互作用的测试。本研究将产生重大的转化影响，因为它将识别与PBC相关的遗传多态性和非核风险因素。通过剖析与PBC进一步研究相关的遗传和环境风险，该研究将成为未来风险评估和疾病预防策略的基础，以及探索涉及牵涉机制的基础研究，并有可能导致对这种毁灭性疾病的新治疗。 公共卫生相关性：这项转化研究旨在检查人类对原发性胆汁肝病（PBC）的敏感性，这是一种慢性自身免疫性肝病，可降低生活质量并缩短预期寿命。我们使用我们最近开发的Mayo诊所PBC遗传流行病学（MCPGE）注册表和生物测试存储库，我们建议研究以鉴定遗传变异和非环境（即环境）危险因素，这些危险因素会导致PBC。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。