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Polymorphisms in the Cytotoxic T Lymphocyte Antigen-4 Gene Region Confer Susceptibility to Addison’s Disease

Institute of Medical Genetics (A.B., H.E.A., D.E.U.), Ullevål University Hospital, University of Oslo, 0315 Oslo, Norway; Institute of Immunology (B.A.L.), Rikshospitalet University Hospital, 0027 Oslo, Norway; Departments of Paediatrics and Clinical Molecular Biology (A.G.M.), Akershus University Hospital, 1474 Nordbyhagen, Norway; Division of Clinical Sciences (North) (E.H.K., A.P.W.), University of Sheffield, Sheffield S5 7AU, United Kingdom; and Division of Endocrinology, Institute of Medicine (E.S.H.), Haukland University Hospital, N-5021 Bergen, Norway

Address all correspondence and requests for reprints to: Dr. Anne Blomhoff, Institute of Medical Genetics, University of Oslo, P.O. Box 1036, Blindern, NO-0315 Oslo, Norway. E-mail: anne.blomhoff{at}ioks.uio.no.

The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison’s disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison’s disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison’s disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.

This work was supported by University of Oslo, Norwegian Diabetes Association, Novo Nordisk Research Foundation, Norwegian Research Council, Haukeland University Hospital, and Innovest.

Abbreviations: APS, Autoimmune polyendocrine syndrome; CTLA4, cytotoxic T lymphocyte antigen-4; HLA, histocompatibility leukocyte antigen; SNP, single nucleotide polymorphism.

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