Dissecting the Aggregation of AMA in Families of PBC Patients

剖析 PBC 患者家庭中 AMA 的聚集情况

• 批准号: 7288655
• 负责人: KONSTANTINOS N LAZARIDIS
• 金额: $ 7.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7288655
• 关键词: Affect; Age; Alkaline Phosphatase; Antibodies; Back; Biochemical; Biochemical Markers; Blood specimen; Cholestasis; Chronic; Cirrhosis; Clinic; DNA; Data; Daughter; Dependence; Development; Disease; Disease Marker; Dissection; Elements; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Etiology; Family; Family Study; Family member; Female; First Degree Relative; Funding; Future; Gender; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Grant; Hepatic; Hormone replacement therapy; Immune; Inherited; Intervention; K-Series Research Career Programs; Knowledge; Life Expectancy; Light; Link; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Mediating; Medical; Mentored Clinical Oncology Award; Mentored Clinical Scientist Award; Mentored Patient-Oriented Research Career Development Award; Mitochondria; Monozygotic Twinning; Monozygotic twins; Mothers; Parents; Pathogenesis; Patients; Phenotype; Play; Predisposition; Prevalence; Primary biliary cirrhosis; Quality of life; Rate; Recording of previous events; Registries; Relative (related person); Research; Resources; Risk; Role; Serological; Serum; Siblings; Sister; Smoking; Specimen; Staging; Study Section; Testing; Time; Urinary tract infection; Ursodeoxycholic Acid; Variant; Whole Blood; Woman; base; bile duct; genetic epidemiology; genetic linkage; genetic pedigree; improved; liver transplantation; microorganism; novel strategies; outcome forecast; proband; repository; segregation; trait; transmission process

DESCRIPTION (provided by applicant): Primary Biliary Cirrhosis (PBC) is an idiopathic, chronic cholestatic liver disease that affects mainly women and predisposes to liver cirrhosis. Despite medical therapy PBC is often progressive, resulting in diminished quality of life and shortening life expectancy. PBC patients display immune-mediated destruction of intra-hepatic bile ducts, persistent biochemical cholestasis, and test positive for serum anti-mitochondrial antibodies (AMA), the serological hallmark of the disease. The assertion that genetic susceptibility, through interaction with environmental exposure, underlies the pathogenesis of PBC is widely accepted. However, the genetic loci contributing to PBC predisposition remain elusive. Our long-term research objective is to better understand the etiology and pathogenesis of PBC in order to improve its prognosis and treatment. To accomplish this objective, we focus on the overall hypothesis, that interplay between identifiable genes and environmental risk factors leads to PBC development. To this extent, we have established the Mayo Clinic PBC Genetic Epidemiology (MCPGE) Registry and Bio-specimen Repository, a large research resource which makes possible the examination and dissection of the genetic and environmental contributors to PBC pathogenesis. Utilizing this resource, it was found that AMA development aggregates among first-degree relatives (FDRs) of PBC probands, with AMA prevalence in these FDRs 13 times higher than in the general population. Since aggregation of AMA in PBC pedigrees does not exclude the influence of common environment shared among family members, the objective of this study is to test the hypothesis that AMA development is a trait which segregates in PBC families, and thus, may play a role in the observed familial risk of PBC. To achieve the objective, this proposal will focus on two Specific Aims: (1) to obtain whole blood specimens from 300 additional FDRs already enrolled into the MCPGE registry to: (i) test them for AMA and liver enzymes (alkaline phosphatase, ALT); and (ii) isolate genomic DNA; and (2) to perform segregation analyses on the AMA phenotype in PBC pedigrees to determine the: (i) overall mode of AMA inheritance; (ii) gender-specific transmission of AMA; (iii) role of age-dependence in AMA development. If development of AMA is shown to be an inherited trait in PBC families, this observation will serve as the basis for a future genetic linkage study of AMA in PBC pedigrees. Such a study will begin to discern the genetic loci contributing to the development of AMA, enabling novel strategies in the dissection of the genetic susceptibility to PBC. Using a large registry and bio-specimen repository of PBC patients and their first-degree relatives, this study will examine whether the development of anti-mitochondrial antibodies (AMA), the serological hallmark of PBC, is genetically inherited in family members of PBC patients. If successful, our effort will shed light toward better understanding of the genetic predisposition to PBC.

描述(由申请人提供)： 原发性胆汁性肝病(PBC)是一种特发性、慢性胆汁淤积性肝病，主要影响女性，易患肝硬变。尽管进行了药物治疗，但PBC往往是渐进性的，导致生活质量下降和预期寿命缩短。PBC患者表现为免疫介导的肝内胆管破坏，持续的生化胆汁淤积，血清抗线粒体抗体(AMA)检测呈阳性，这是该病的血清学标志。通过与环境接触的相互作用，遗传易感性是PBC发病机制的基础，这一断言被广泛接受。然而，导致PBC易感性的遗传位点仍然难以捉摸。我们的长期研究目标是更好地了解PBC的病因和发病机制，以改善其预后和治疗。为了实现这一目标，我们将重点放在总体假设上，即可识别的基因和环境风险因素之间的相互作用导致PBC的发展。为此，我们建立了梅奥诊所PBC遗传流行病学(MCPGE)登记处和生物标本库，这是一个大型研究资源，使检查和剖析PBC发病的遗传和环境因素成为可能。利用这一资源，研究发现，AMA发育集中在PBC先证者的一级亲属(FDR)中，这些FDR中AMA的患病率是普通人群的13倍。由于AMA在PBC家系中的聚集不排除家庭成员共同环境的影响，本研究的目的是验证AMA发育是PBC家族中分离的性状的假设，从而可能在观察到的PBC家族风险中发挥作用。为了实现这一目标，这项建议将集中于两个具体目标：(1)从已登记在MCPGE登记处的另外300个FDR中获取全血样本，以：(I)检测AMA和肝酶(碱性磷酸酶，ALT)；以及(Ii)分离基因组DNA；以及(2)对PBC家系中的AMA表型进行分离分析，以确定：(I)AMA遗传的总体模式；(Ii)AMA的性别传播；(Iii)年龄依赖在AMA发展中的作用。如果AMA的发育被证明是PBC家系的一种遗传性状，这一观察结果将为今后PBC家系中AMA的遗传连锁研究奠定基础。这样的研究将开始辨别有助于AMA发展的遗传位点，使在解剖PBC遗传易感性方面的新策略成为可能。利用PBC患者及其一级亲属的大型登记和生物标本库，这项研究将检查PBC的血清学标志-抗线粒体抗体(AMA)的发展是否在PBC患者的家庭成员中遗传。如果成功，我们的努力将有助于更好地理解PBC的遗传易感性。