Dissecting the Aggregation of AMA in Families of PBC Patients

描述（由申请人提供）： 原发性胆汁性肝硬化（PBC）是一种原发性慢性胆汁淤积性肝病，主要影响女性，易发生肝硬化。尽管有药物治疗，PBC通常是进行性的，导致生活质量下降和预期寿命缩短。PBC患者表现出免疫介导的肝内胆管破坏、持续的生化胆汁淤积和血清抗线粒体抗体（AMA）测试阳性，这是该疾病的血清学标志。遗传易感性通过与环境暴露的相互作用而成为PBC发病机制的基础的论断被广泛接受。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，我们专注于整体假设，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，我们建立了马约诊所PBC遗传流行病学（MCPGE）登记和生物标本库，这是一个大型研究资源，可以检查和解剖PBC发病机制的遗传和环境因素。利用这一资源，发现AMA的发展聚集在PBC先证者的一级亲属（FDR）中，这些FDR中的AMA患病率比一般人群高13倍。由于PBC家系中AMA的聚集并不排除家庭成员之间共享的共同环境的影响，因此本研究的目的是检验AMA的发展是PBC家族中分离的一个特征，因此可能在观察到的PBC家族风险中发挥作用的假设。为了实现这一目标，本提案将侧重于两个具体目标：（1）从已入组MCPGE登记研究的另外300名FDR中获取全血样本，以：（i）检测AMA和肝酶（ii）分离基因组DNA;和（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的性别特异性传播;（iii）年龄依赖在AMA发展中的作用。如果AMA的发展被证明是PBC家族的遗传特征，这一观察结果将作为未来PBC家系AMA遗传连锁研究的基础。这样的研究将开始辨别有助于AMA发展的遗传位点，从而在PBC遗传易感性的解剖中实现新的策略。使用PBC患者及其一级亲属的大型注册表和生物标本库，本研究将检查PBC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了解PBC的遗传易感性。

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.