Genomics of Primary Biliary Cirrhosis

原发性胆汁性肝硬化的基因组学

• 批准号: 8240466
• 负责人: KONSTANTINOS N LAZARIDIS
• 金额: $ 29.62万
• 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 2013-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240466
• 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 strategy; Prevention therapy; 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; 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（申请人提供）：原发性胆汁性肝硬化（PBC）的遗传和非遗传风险因素尚未得到充分研究。因此，这种慢性胆汁淤积性肝病的原因和发病机制仍不清楚，PBC继续降低生活质量，并减少许多妇女的预期寿命，这些妇女是这种疾病的主要患者。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，我们创建了马约诊所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，年龄（+2.5岁），性别，种族和居住州分别匹配。PBC的遗传易感性的概念是公认的，并被广泛接受。最近，PBC的小鼠模型（NOD.c3c4）被用来确定自身免疫性胆道疾病1（Abd 1）基因座。尽管取得了进展，但PBC的遗传易感性、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细致的调查。在本申请中，我们希望通过利用MCPGE研究资源的500个病例和500个对照来检验人免疫组（即编码免疫系统的必需组分的已知基因的总和）和与鼠Abd 1基因座同源的人基因的遗传变体（即单核苷酸多态性-SNP）与PBC相关的假设。本研究的具体目的是：目的1：我们将使用847个免疫基因的定制SNP阵列对病例和对照进行基因分型（10，734个SNP）并进行遗传关联分析;目的2我们将用与鼠Abd 1基因座同源的250个人类基因的定制SNP阵列对病例和对照进行基因分型（4，337个SNP）并进行遗传关联分析;目标3：（a）验证PBC的拟议风险因素（即吸烟、尿路感染、激素替代疗法）并评估新的假定风险因素（即二手烟、水源、农药暴露）;以及（B）测试环境暴露与发现与目标1和2中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转化影响，因为它将确定与PBC相关的遗传多态性和非遗传性危险因素。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，以及探索相关机制并可能导致这种毁灭性疾病的新疗法的基础研究。 公共卫生相关性：这项翻译研究旨在研究人类对原发性胆汁性肝硬化（PBC）的易感性，PBC是一种慢性自身免疫性肝病，会降低生活质量并缩短预期寿命。使用我们最近开发的马约诊所PBC遗传流行病学（MCPGE）登记和生物标本库，我们提出的研究，以确定遗传变异和非遗传（即环境）的危险因素，有助于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。