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

Genes & Immunity volume 4, pages 586–593 (2003)Cite this article

Abstract

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.

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Acknowledgements

This work was supported in part by DK35764, DK45011 and DK52464 from NIDDKD (to TFD), DK31775, NS27941, and MH48858 (to DAG), DK02498 and DK58072 from NIDDKD (to YT). This work was presented in part at the 85th Annual Meeting of the Endocrine Society, June 2003, Philadelphia.

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine Box 1055, New York, NY, USA

    Y Ban, T F Davies, A Kissin, E S Concepcion, R B Villanueva, G Barbesino & Y Tomer

  2. Division of Statistical Genetics, Columbia University New York, NY, USA

    D A Greenberg

  3. Division of Nephrology, Mount Sinai School of Medicine, New York, NY, USA

    B Marder & B Murphy

  4. Department of Inflammation Biology, Biotechnology Group, Wyeth Research, Cambridge, MA, USA

    V Ling

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Correspondence to Y Ban.

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Ban, Y., Davies, T., Greenberg, D. et al. Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease. Genes Immun 4, 586–593 (2003). https://doi.org/10.1038/sj.gene.6364018

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