Abstract：
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 antimitochondrial 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.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Juran BD,Atkinson EJ,Schlicht EM,Fridley BL,Lazaridis KNdoi
10.1053/j.gastro.2008.06.077subject
Has Abstractpub_date
2008-10-01 00:00:00pages
1200-6issue
4eissn
0016-5085issn
1528-0012pii
S0016-5085(08)01146-3journal_volume
135pub_type
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