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Association of Type 1 Diabetes with Two Loci on 12q13 and 16p13 and the Influence Coexisting Thyroid Autoimmunity in Japanese

Division of Endocrinology and Diabetes, Department of Medicine (T.A., S.Ku., M.O., S.Ka.), and Division of RI Laboratory (T.A., H.Ii.), Biomedical Research Center, Saitama Medical University, Saitama 350-0495, Japan; Department of Metabolism/Diabetes and Clinical Nutrition (E.K., M.U.), Nagasaki University Hospital of Medicine and Dentistry, Nagasaki 852-8501, Japan; Third Department of Internal Medicine (S.T., T.K.), Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan; Department of Endocrinology, Metabolism, and Diabetes (H.Ik., Y.Kaw.), Kinki University School of Medicine, Osaka 589-8511, Japan; Department of Internal Medicine (T.M.), Saitama Social Insurance Hospital, Saitama 330-0074, Japan; Department of Internal Medicine (A.S., Y.Kan.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Endocrinology and Metabolism (K.N.), Toranomon Hospital, Tokyo 160-8582, Japan

Address all correspondence and requests for reprints to: Takuya Awata, Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama, 350-0495, Japan. E-mail: awata{at}saitama-med.ac.jp.

Context: Recent genome-wide association studies have identified several novel type 1 diabetes (T1D) loci in white populations.

Objective: In line with recent findings, we conducted a replication study of two loci on chromosome 12p13 and 16p13 and assessed their potential associations with thyroid autoimmunity in a Japanese population.

Subjects and Methods: Two single-nucleotide polymorphisms (SNPs), rs2292399 in ERBB3 on 12q13 and rs2903692 in CLEC16A (or KIAA0350) on 16p13, were analyzed in Japanese subjects consisting of 735 T1D patients, 330 patients with autoimmune thyroid disease (AITD), and 621 control subjects.

Results: According to a case-control study and logistic regression adjusting for sex and age, we observed that these SNPs in ERBB3 and CLEC16A were both significantly associated with T1D, with the risk alleles being consistent with those in white populations [adjusting odds ratio by multiplicative model: 1.37 (1.13–1.67), P = 0.001; and 1.28 (1.02–1.60), P = 0.030, respectively]. In both SNPs, the association was suggested to be stronger in T1D complicated with AITD (Graves’ disease, Hashimoto’s thyroiditis, or thyroid autoantibodies). Furthermore, a joint analysis, with the INS and CTLA4 SNPs, revealed that CTLA4 rs3087243, ERBB3 rs2292399, and CLEC16A rs2903692, but not INS rs689, were significant risk factors for the cooccurrence of AITD in Japanese T1D.

Conclusion: We confirmed two loci on 12q13 and 16p13 that were identified by the independent genome-wide association studies in white populations, thus suggesting that these loci contribute to T1D susceptibility across different ethnic groups. In addition, these loci may also be associated with the cooccurrence of thyroid autoimmunity in T1D.