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Association Analysis of the Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Autoimmune Regulator-1 (AIRE-1) Genes in Sporadic Autoimmune Addison’s Disease¹

Endocrine Group, Department of Medicine, University of Newcastle upon Tyne (B.V., H.I., D.R.G., S.G.B., P.H.B., R.A.J., P.K.-T., S.H.S.P.), Newcastle upon Tyne NE2 4HH; Department of Medicine, Freeman Hospital (P.P.), Newcastle upon Tyne NE7 7DN; Division of Medicine, North Tees General Hospital (D.C.), Stockton on Tees TS19 8PE; Department of Medicine, University College and Middlesex Hospital (S.J.H.), London W1N 8AA; Diabetes Care Centre, Middlesbrough General Hospital (W.F.K.), Middlesbrough TS5 5AZ; Division of Clinical Sciences, University of Sheffield (E.H.K., A.P.W.), Sheffield 55 7AU; Department of Medicine, Wansbeck General Hospital (E.T.Y.), Ashington NE63 9JJ, United Kingdom

Address correspondence and requests for reprints to: Dr. Simon Pearce, Department of Medicine, 4th Floor Leech Building, The Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: spearce{at}hgmp.mrc.ac.uk

Although autoimmune Addison’s disease (AAD) may occur as a component of the monogenic autoimmune polyendocrinopathy type 1 syndrome (APS1), it is most commonly found as an isolated disorder or associated with the autoimmune polyendocrinopathy type 2 syndrome (APS2). It is likely that sporadic (non-APS1) AAD is inherited as a complex trait; however, apart from the major histocompatibility complex, the susceptibility genes remain unknown. We have examined polymorphisms at two non-major histocompatibility complex candidate susceptibility loci in sporadic (non-APS1) AAD: the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and the autoimmune regulator (AIRE-1) gene. DNA samples from AAD subjects (n = 90) and local controls (n = 144 for CTLA-4; n = 576 for AIRE-1) were analyzed for the CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene and for the common mutant AIRE-1 allele (964del13) in United Kingdom subjects with APS1, by using the restriction enzymes Bst71I and BsrBI, respectively. There was an association of the G allele at CTLA-4A/G in AAD subjects (P = 0.008 vs. controls), which was stronger in subjects with AAD as a component of APS2 than in subjects with isolated AAD. In contrast, the mutant AIRE-1 964del13 allele was carried in one each of the 576 (0.2%) control subjects and the 90 (1.1%) AAD subjects as a heterozygote (P = 0.254, not significant), suggesting that this common AIRE-1 gene abnormality does not have a major role in sporadic (non-APS1) AAD.

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