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Analysis of Immune Regulatory Genes in Familial and Sporadic Graves’ Disease

Division of Endocrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine (Y.B., E.S.C., R.V., T.F.D., Y.T.), New York, New York 10029; and Division of Statistical Genetics, Columbia University (D.A.G.), New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Yaron Tomer, Division of Endocrinology, Diabetes, and Bone Diseases, Box 1055, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029. E-mail: yaron.tomer{at}mssm.edu.

Graves’ disease (GD) is seen in apparently sporadic and familial forms. At least two immune regulatory genes are associated with GD, human leukocyte antigen (HLA) and cytotoxic T lymphocyte antigen-4 (CTLA-4). The aim of our study was to examine the contributions of HLA and CTLA-4 to the familial clustering of GD by analyzing them for association with familial and sporadic GD. We analyzed 160 Caucasian GD patients (69 familial and 91 sporadic), and 150 matched controls. Analysis of all GD patients demonstrated significant associations between GD and HLA-DR3 [P = 9.0 x 10^–7; relative risk (RR) = 3.8] and two CTLA-4 single nucleotide polymorphisms (SNPs), A/G₄₉ SNP (P = 0.03; RR = 1.5), and CT60 SNP (P = 0.03; RR = 1.4). Moreover, there was evidence for joint susceptibility to risk between HLA-DR3 and CTLA-4, giving a combined RR of 5.9. Subset analysis demonstrated no significant difference between the frequencies of HLA-DR3 and the susceptibility alleles of CTLA-4 A/G₄₉ and CT60 SNPs in the familial and sporadic GD subsets (P > 0.05). These results suggested that HLA-DR3 and CTLA-4 conferred a general increased risk for GD in both the sporadic and familial forms, and that the risk conferred by them was additive. However, HLA-DR3 and CTLA-4 did not have a stronger effect in the familial GD patients, suggesting that additional genes must contribute to the aggregation of GD within families.

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