Dissecting the Aggregation of AMA in Families of PBC Patients

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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.