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, χ2 = 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, χ2 = 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 HLADRB1*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.

[1]  M. Friedman.  Thyroid autoimmune disease. , 2013, The Mount Sinai journal of medicine, New York.

[2]  G. Gerken,et al.  Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. , 2008, Liver.

[3]  M. Juan,et al.  Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. , 2001, The American journal of pathology.

[4]  S. Pearce,et al.  CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. , 2000, Journal of hepatology.

[5]  P. Donaldson,et al.  Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis , 1999, Hepatology.

[6]  P. Donaldson,et al.  Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. , 1999, Gastroenterology.

[7]  K. Becker,et al.  Comparative genetics of type 1 diabetes and autoimmune disease: common loci, common pathways? , 1999, Diabetes.

[8]  G. Le Gros,et al.  The role of CTLA‐4 in the regulation of T cell immune responses , 1999, Immunology and cell biology.

[9]  J. Trent,et al.  Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  C. Benoist,et al.  Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Regulates the Unfolding of Autoimmune Diabetes , 1998, The Journal of experimental medicine.

[11]  J. Heward,et al.  Genetic susceptibility to the development of autoimmune disease. , 1997, Clinical science.

[12]  J. Allison,et al.  The emerging role of CTLA-4 as an immune attenuator. , 1997, Immunity.

[13]  J. Rotter,et al.  Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. , 1997, Human molecular genetics.

[14]  L. Thomson,et al.  Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. , 1997, Gastroenterology.

[15]  T. Strom,et al.  Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. , 1997, Immunity.

[16]  J. Bluestone.  Is CTLA-4 a master switch for peripheral T cell tolerance? , 1997, Journal of immunology.

[17]  L. Thomson,et al.  Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis , 1997, Hepatology.

[18]  A. Czaja,et al.  Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis , 1996, Hepatology.

[19]  C. June,et al.  CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. , 1996, Journal of immunology.

[20]  J. Todd,et al.  The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. , 1996, Human molecular genetics.

[21]  H. Griesser,et al.  Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4 , 1995, Science.

[22]  M. Manns,et al.  The validity and importance of subtypes in autoimmune hepatitis: a point of view. , 1995, The American journal of gastroenterology.

[23]  M. Nishioka,et al.  Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis. , 1994, Gastroenterology.

[24]  G. Mieli-Vergani,et al.  T-cell receptor constant beta germline gene polymorphisms and susceptibility to autoimmune hepatitis. , 1994, Gastroenterology.

[25]  Roger Williams,et al.  Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis , 1994, Hepatology.

[26]  A. Czaja,et al.  Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. , 1993, Gastroenterology.

[27]  A. Czaja,et al.  Significance of HLA DR4 in type 1 autoimmune hepatitis. , 1993, Gastroenterology.

[28]  P. Johnson,et al.  Meeting report: International autoimmune hepatitis group , 1993, Hepatology.

[29]  M. Manns,et al.  Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. , 1992, Gastroenterology.

[30]  M. Manns,et al.  Clonal analysis of liver‐infiltrating T cells in patients with LKM‐1 antibody‐positive autoimmune chronic active hepatitis , 1991, Clinical and experimental immunology.

[31]  Roger Williams,et al.  Susceptibility to autoimmune chronic active hepatitis: Human leukocyte antigens DR4 and A1‐B8‐DR3 are independent risk factors , 1991, Hepatology.

[32]  D. Vergani,et al.  T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis , 1990, The Lancet.

[33]  F. Alvarez,et al.  Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: A second type of “autoimmune” hepatitis , 1987, Hepatology.

[34]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[35]  T. Bird,et al.  Evaluation of a tanned red cell technique for thyroid microsomal antibodies , 1973, Journal of clinical pathology.

[36]  I. Doniach.  PRIMARY HYPERPARATHYROIDISM: A CRITICAL REVIEW , 1967 .

[37]  D. Doniach,et al.  A stable sheep cell preparation for detecting thyroglobulin auto-antibodies and its clinical applications , 1961, Journal of clinical pathology.

[38]  K. Meyer zum Büschenfelde,et al.  Limited T cell receptor Vbeta-chain repertoire of liver-infiltrating T cells in autoimmune hepatitis. , 1998, Journal of hepatology.

[39]  R. Hultcrantz,et al.  CTLA-4 gene polymorfism associated with primary sclerosing cholangitis (PSC) , 1998 .

[40]  K. Usadel,et al.  CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. , 1997, The Journal of clinical endocrinology and metabolism.

[41]  I. Mackay,et al.  Interaction of HLA and Gm in autoimmune chronic active hepatitis. , 1981, Clinical and experimental immunology.