• Selmi, Carlo F (PI)

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a striking female predominance. Although the etiology remains enigmatic, genetic susceptibility is supported by several lines of evidence: a) the concordance rate of PBC in monozygotic (MZ) twins is 63%; b) 6% of patients with PBC have a first-degree relative that also suffers from PBC, and finally and most importantly, c) women with PBC or two other female-predominant autoimmune diseases have a significantly enhanced monosomy X frequency in peripheral white blood cells compared to age- and disease stage-matched women with chronic viral hepatitis and to age-matched healthy women. Accordingly, genetic background appears necessary, yet not sufficient, to explain PBC susceptibility nor the female predominance. Epigenetics are an excellent model for studying the genome-environment interaction and are therefore applicable to complex autoimmune diseases; the random X chromosome inactivation (XCI) in women is caused by epigenetic mechanisms such as DNA methylation. However, there are 125 X-linked genes that exhibit widely variable patterns of inactivation between individuals. We hypothesize that susceptibility to PBC arises from individual epigenetic modifications of specific genes on the X chromosome, either with protective genes being silenced or susceptibility genes escaping inactivation. Our aims will be two-fold: (1) is there an altered expression of the 125 differentially inactivated X-linked genes in women with PBC? In particular, we will perform RT-PCR analysis in 30 PBC discordant sibling pairs as well as 3 concordant and 3 discordant MZ twin pairs; (2) what is the methylation pattern of the genes differentially expressed in affected and unaffected MZ twins by bisulfite sequencing? This proposal brings together evidence on enhanced monosomy X in autoimmunity and variable X chromosome inactivation patterns, as well as taking advantage of a unique series of MZ twins and siblings concordant and discordant for PBC to focus on a question that is likely to have implications also for other autoimmune disorders.
Effective start/end date9/22/068/31/09


  • National Institutes of Health: $184,490.00
  • National Institutes of Health: $189,479.00


  • Medicine(all)


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