Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.

[1]  S. Rich,et al.  Association of autoimmune thyroid disease with a microsatellite marker for the thyrotropin receptor gene and CTLA-4 in a Japanese population. , 1997, Proceedings of the Association of American Physicians.

[2]  J. Franklyn,et al.  The development of Graves' disease and the CTLA-4 gene on chromosome 2q33. , 1999, The Journal of clinical endocrinology and metabolism.

[3]  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.

[4]  S. Lehar,et al.  The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. , 2000, Immunity.

[5]  K. Usadel,et al.  Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease. , 1997, The Journal of clinical endocrinology and metabolism.

[6]  S. Rich,et al.  Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients. , 2000, Thyroid : official journal of the American Thyroid Association.

[7]  M. Fisfalen,et al.  CTLA-4 Gene Polymorphism at Position 49 in Exon 1 Reduces the Inhibitory Function of CTLA-4 and Contributes to the Pathogenesis of Graves’ Disease1 , 2000, The Journal of Immunology.

[8]  S. S. Stoffer,et al.  Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text , 2001 .

[9]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[10]  K. Usadel,et al.  CTLA-4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis. , 1998, Tissue antigens.

[11]  D. Pauls,et al.  Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic "fingerprints". , 1999, The Journal of clinical endocrinology and metabolism.

[12]  G. Barbesino,et al.  Limited genetic susceptibility to severe Graves' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. , 2000, Thyroid : official journal of the American Thyroid Association.

[13]  Cécile Fizames,et al.  A comprehensive genetic map of the human genome based on 5,264 microsatellites , 1996, Nature.

[14]  Paul W. Wu,et al.  Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches. , 2001, Genomics.

[15]  L Kruglyak,et al.  Parametric and nonparametric linkage analysis: a unified multipoint approach. , 1996, American journal of human genetics.

[16]  K. Kotsa,et al.  A CTLA‐4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidism , 1997, Clinical endocrinology.

[17]  G. Barbesino,et al.  The Immunogenetics of Autoimmune Diabetes and Autoimmune Thyroid Disease , 1997, Trends in Endocrinology & Metabolism.

[18]  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.

[19]  T. Yanagawa,et al.  CTLA-4 gene polymorphism associated with Graves' disease in a Caucasian population. , 1995, The Journal of clinical endocrinology and metabolism.

[20]  L. Hegedüs,et al.  What is the evidence of genetic factors in the etiology of Graves' disease? A brief review. , 1998, Thyroid : official journal of the American Thyroid Association.

[21]  J. Franklyn,et al.  Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom. , 2002, Thyroid : official journal of the American Thyroid Association.

[22]  Barnett,et al.  No evidence for allelic association of a human CTLA‐4 promoter polymorphism with autoimmune thyroid disease in either population‐based case–control or family‐based studies , 1998, Clinical endocrinology.

[23]  N. Rose,et al.  The presence of thyroid autoantibodies in children and adolescents with autoimmune thyroid disease and in their siblings and parents. , 1982, Clinical immunology and immunopathology.

[24]  P. O'Connell,et al.  Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping. , 1993, American journal of human genetics.

[25]  P. Rieckmann,et al.  A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation , 2002, Immunogenetics.

[26]  R. Pirskanen,et al.  Dinucleotide repeat expansion in the CTLA-4 gene leads to T cell hyper-reactivity via the CD28 pathway in myasthenia gravis , 2000, Journal of Neuroimmunology.

[27]  E. Young,et al.  Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. , 1990, The Journal of clinical endocrinology and metabolism.

[28]  J. Ott,et al.  A computer program for linkage analysis of general human pedigrees. , 1976, American journal of human genetics.

[29]  W Harry Hannon,et al.  Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). , 2002, The Journal of clinical endocrinology and metabolism.

[30]  J. Hillert,et al.  CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms , 2001, Genes and Immunity.

[31]  R Volpé,et al.  Autoimmune thyroid disease. , 1984, Hospital practice.

[32]  D. Appleton,et al.  THE SPECTRUM OF THYROID DISEASE IN A COMMUNITY: THE WHICKHAM SURVEY , 1977, Clinical endocrinology.

[33]  A population-based study of chronic autoimmune hypothyroidism in Danish twins. , 2000, The Journal of clinical endocrinology and metabolism.

[34]  J. Koh,et al.  Polymorphism in the promoter and exon 1 of the cytotoxic T lymphocyte antigen-4 gene associated with autoimmune thyroid disease in Koreans. , 2000, Thyroid : official journal of the American Thyroid Association.

[35]  J. Franklyn,et al.  MHC class II region, CTLA4 gene, and ophthalmopathy in patients with Graves' disease , 2001, The Lancet.

[36]  M. McCarthy,et al.  The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus. , 1999, Human molecular genetics.

[37]  Andreas Hutloff,et al.  ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 , 1999, Nature.

[38]  W S Watkins,et al.  Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. , 1994, American journal of human genetics.

[39]  J. Partanen,et al.  Technical Note: Linkage Disequilibrium and Disease-Associated CTLA4 Gene Polymorphisms , 2001, The Journal of Immunology.

[40]  L. Nisticò,et al.  Association of DRB1*04-DQB1*0301 haplotype and lack of association of two polymorphic sites at CTLA-4 gene with Hashimoto's thyroiditis in an Italian population. , 2001, Thyroid : official journal of the American Thyroid Association.

[41]  Y. Tomer,et al.  CTLA-4 and autoimmune thyroid disease: lack of influence of the A49G signal peptide polymorphism on functional recombinant human CTLA-4. , 2002, Cellular immunology.

[42]  J. Stanbury,et al.  Familial studies of autoimmune thyroiditis. , 1967, Clinical and experimental immunology.

[43]  K. Zaletel,et al.  The influence of the exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene on thyroid antibody production in patients with newly diagnosed Graves' disease. , 2002, Thyroid : official journal of the American Thyroid Association.

[44]  F. Pociot,et al.  CTLA-4 in autoimmune diseases – a general susceptibility gene to autoimmunity? , 2000, Genes and Immunity.

[45]  R. Pirskanen,et al.  Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence , 2002, Journal of Neuroimmunology.

[46]  M. McCarthy,et al.  Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy , 1999, The Lancet.

[47]  P. McGuffin,et al.  Complex segregation analysis of thyroid autoantibodies: are they inherited as an autosomal dominant trait? , 1993, Human Heredity.

[48]  G. Barbesino,et al.  CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production. , 2001, The Journal of clinical endocrinology and metabolism.

[49]  G. Daniels,et al.  Chronic autoimmune thyroiditis. , 1996, The New England journal of medicine.

[50]  D. Pauls,et al.  Complex segregation analysis of antibodies to thyroid peroxidase in Old Order Amish families. , 1993, American journal of medical genetics.

[51]  T. Saruta,et al.  CTLA4 gene polymorphism confers susceptibility to Graves' disease in Japanese. , 1997, Thyroid : official journal of the American Thyroid Association.

[52]  Y. Tomer,et al.  Unraveling the genetic susceptibility to autoimmune thyroid diseases: CTLA-4 takes the stage. , 2001, Thyroid : official journal of the American Thyroid Association.