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      Graves’ Disease in Brazilian Children and Adults: Lack of Genetic Association with CTLA-4 +49A>G Polymorphism

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          Abstract

          Background/Aim: In several populations, major histocompatibility complex and CTLA-4 (cytotoxic T lymphocyte antigen-4) gene polymorphisms are related to adult subjects with Graves’ disease (GD). Our aim was to study the association of +49A>G polymorphism of the CTLA-4 gene in Brazilian children and adults with GD and its correlation with clinical and laboratory markers of disease severity. Methods: CTLA-4 +49A>G polymorphism was established by polymerase chain reaction-restriction fragment length polymorphism analysis in 44 children and 72 adults with GD and compared to a stringent control group consisting of octogenarians with no history of thyroid disease; free T<sub>4</sub> and T<sub>3</sub> levels and T<sub>3</sub>/T<sub>4</sub> ratio, antithyroid antibodies, and Graves’ ophthalmopathy were also evaluated according to genotype. Results: No significant difference was found in the frequency of CTLA-4 +49A>G polymorphism among children and adults with GD compared to controls and within groups. There was no significant correlation between the presence of G allele and Graves’ ophthalmopathy, gender, age at diagnosis, and biochemical markers of disease severity. Conclusion: The frequency of CTLA-4 +49A>G polymorphism is not different in children and adults with GD compared to the normal control population and does not seem to contribute independently to the severity of the clinical presentation of GD.

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          The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry.

          F Gorus, Antonia Pritchard, Travis P. Todd … (1996)
          Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ-specific autoimmune disease.
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            T-cell costimulation--biology, therapeutic potential, and challenges.

            Hamed Abbas, Katharine Sharpe (2006)
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              The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan.

              Shoichiro Tanaka, Y Kanazawa, Takuya Awata … (2006)
              Transracial studies are a powerful tool for genetic association studies of multifactorial diseases, such as type 1 diabetes. The low incidence of type 1 diabetes in Asian countries, however, makes it difficult to perform large-scale studies in Asia. To overcome this, we have assembled a multicenter study group in Japan and studied the association of CTLA4 polymorphisms with type 1 diabetes relative to autoimmune thyroid disease (AITD) phenotypes. Subjects included a total of 1837 samples, including 1114 cases (769 with type 1 diabetes and 345 with AITD) and 723 control subjects. The +6230G>A and +49G>A polymorphisms of CTLA4 as well as HLA-DRB1 and -DQB1 were genotyped. The +6230G>A polymorphism was significantly associated with type 1 diabetes complicated with AITD (odds ratio, 1.54; P = 0.027) and with AITD alone (odds ratio, 1.31; P = 0.045) but not with type 1 diabetes without AITD. The association with type 1 diabetes positive for autoantibodies to both pancreatic islets and thyroid was particularly strong (odds ratio, 1.87; P = 0.001). Type 1 diabetic patients with the disease-associated GG genotype were characterized by a significantly higher frequency of AITD (P = 0.013), of positivity for both AITD and antiislet autoantibody (P = 0.00086), and of high-risk HLA genotypes (P = 0.034). Given the high frequency of AITD in patients with type 1 diabetes, these data suggest the possibility that the association of CTLA4 with type 1 diabetes in previous studies may have been secondary to AITD, suggesting the importance of subclassification of type 1 diabetes relative to AITD in genetic studies.
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                Author and article information

                Journal
                Journal ID (publisher-id): HRE
                Journal ID (nlm-ta): Horm Res Paediatr
                Journal ID (doi): 10.1159/issn.1663-2818
                Title: Hormone Research in Paediatrics
                Publisher: S. Karger AG
                ISSN (Print): 1663-2818
                ISSN (Electronic): 1663-2826
                Publication date Subscription-year: 2008
                Publication date (Print): July 2008
                Publication date (Electronic): 21 May 2008
                Volume: 70
                Issue: 1
                Pages: 36-41
                Affiliations
                aEndocrine and Metabolic Unit and bPediatric Endocrinology Unit, Santa Casa de São Paulo, and cMolecular Medicine Laboratory, Department of Physiology, Santa Casa de São Paulo Faculty of Medical Sciences, São Paulo, Brazil
                Article
                Publisher ID: 129676 Other ID: Horm Res 2008;70:36–41
                DOI: 10.1159/000129676
                PubMed ID: 18493148
                SO-VID: 52ef26b2-e655-4628-8f9e-aee195bafe9e
                Copyright © © 2008 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 27 March 2007
                Date accepted : 09 July 2007
                Page count
                Tables: 3, References: 39, Pages: 6
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Keywords: Graves’ disease,Cytotoxic T lymphocyte antigen-4 gene polymorphism,Children, Graves’ disease
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes, Neurology, Nutrition & Dietetics, Sexual medicine, Internal medicine, Pharmacology & Pharmaceutical medicine
                Keywords: Graves’ disease, Cytotoxic T lymphocyte antigen-4 gene polymorphism, Children, Graves’ disease

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