Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)‐guanine (G) base‐exchange polymorphism for CTLA‐4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically‐matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA = 50/155 patients vs. 51/102 controls; AG = 84/155 patients vs. 38/102 controls; GG = 21/155 patients vs. 13/102 controls, χ 2 = 8.94, P = .011). This difference was caused by a significant over‐representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, χ 2 = 8.34, P = .004, odds ratio = 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level ( P = .03), greater frequency of antibodies to thyroid microsomal antigens ( P = .004) and was found more commonly in patients with HLA DRB1*0301 ( P = .02). Treatment outcomes, however, were not affected by the genotype. The CTLA‐4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA‐DRB1*0301 and the GG genotype in terms of disease risk.