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CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis

Lookup NU author(s): Professor David Jones, Professor Ann DalyORCiD, Emeritus Professor Oliver James, Dr Bijayeswar Vaidya, Professor Simon PearceORCiD, Professor Margaret Bassendine


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Background/Aim: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease thought to develop through a complex interaction of genetic and environmental factors. It is characterised by T-cell-mediated non-suppurative destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital negative regulator of T-cell activation, as a candidate susceptibility locus for PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with susceptibility to both type 1 diabetes and autoimmune thyroid disease. Methods: The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine, respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC patients and 200 non-related geographically matched Caucasoid controls. Results: There was significant overrepresentation of the G/A and G/G genotypes in PBC patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio (OR)=2.45 [95% CI 1.6-3.7], p=0.00006, χ2=19.4). Likewise, there was a significant difference in allele frequencies (G encoding alanine at codon 17, PBC 0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained significant (p=0.00027) when patients with autoimmune thyroid disease were excluded from the analysis. Conclusions: The CTLA-4 exon 1 polymorphism is the first non- major histocompatibility complex gene to be identified as a susceptibility locus for PBC. Our data support the hypothesis that clinically distinct autoimmune disease may be controlled by a common set of susceptibility genes.

Publication metadata

Author(s): Agarwal K, Jones DEJ, Daly AK, James OFW, Vaidya B, Pearce S, Bassendine MF

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2000

Volume: 32

Issue: 4

Pages: 538-541

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier B.V.


DOI: 10.1016/S0168-8278(00)80213-5

PubMed id: 10782900


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