Background/Aim: Primary biliary cirrhosis (PBC) is an autoimmune cholestati
c liver disease thought to develop through a complex interaction of genetic
and environmental factors. It is characterised by T-cell-mediated non-supp
urative destructive cholangitis. We have studied the polymorphic cytotoxic
T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule t
hat is a vital negative regulator of T-cell activation, as a candidate susc
eptibility locus for PBC, This gene on chromosome 2q33 (designated IDDM12)
is associated with susceptibility to both type 1 diabetes and autoimmune th
yroid disease.
Methods: The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alan
ine, respectively) was genotyped via polymerase chain reaction in 200 Cauca
soid PBC patients and 200 non-related geographically matched Caucasoid cont
rols.
Results: There was significant overrepresentation of the G/A and G/G genoty
pes 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, chi(2)=19.4). Likewi
se, there was a significant difference in allele frequencies (G encoding al
anine 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 autoi
mmune thyroid disease were excluded from the analysis.
Conclusions: The CTLA-4 exon 1 polymorphism is the first non-major histocom
patibility complex gene to be identified as a susceptibility locus for PBC,
Our data support the hypothesis that clinically distinct autoimmune diseas
e may be controlled by a common set of susceptibility genes.