Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene

Background & Aims: Genetic variation is invoked as a strong component underlying primary biliary cirrhosis (PBC) and other autoimmune disorders. Data suggest that some of this genetic risk is shared, affecting function of the immune mechanisms controlling self-tolerance. Cytotoxic T-lymphocyte antigen 4 (CTLA4) encodes a coinhibitory immunoreceptor that is a key regulator of self-tolerance with established genetic associations to multiple autoimmune diseases but conflicting evidence of involvement with PBC. We aimed to perform a more comprehensive assessment of CTLA4 genetic variation in PBC using a haplotype-tagging based approach. Methods: Single nucleotide polymorphisms (SNPs) were genotyped in 402 PBC patients and 279 controls and evaluated for association with PBC and with anti-mitochondrial antibody (AMA) status and prior orthotopic liver transplantation (OLT) among the PBC patients, both individually and as inferred haplotypes, using logistic regression. Results: All SNPs were in Hardy-Weinberg equilibrium. We identified a novel and relatively strong association between PBC and rs231725, a SNP in the 3' flanking region of CTLA4 located outside of the area previously investigated in PBC. This SNP tags a common CTLA4 haplotype that contains a number of functionally implicated autoimmune CTLA4 SNPs, which was also found to be associated with PBC and to a lesser extent AMA status and prior OLT. Conclusions: Our findings suggest that CTLA4 has an impact on the risk of PBC and possibly plays a role in influencing AMA development as well as progression to OLT among PBC patients. Replication in a suitable, independent PBC cohort is needed.