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, chi(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, chi(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.
Agarwal
K
K
Centre for Liver Research, Faculty of Clinical Medical Sciences, The Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne, UK.
Czaja
A J
AJ
Jones
D E
DE
Donaldson
P T
PT
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001379:Azathioprine / Q000627:therapeutic use; D060908:CTLA-4 Antigen; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011241:Prednisone / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D001379:Azathioprine; D011241:Prednisone