Analysis of the HLA and non-HLA susceptibility loci in Japanese type 1 diabetes

• Published in: Diabetes/metabolism research and reviews Vol. 27; no. 8; pp. 844 - 848
• Main Authors: Yamashita, Hisakuni, Awata, Takuya, Kawasaki, Eiji, Ikegami, Hiroshi, Tanaka, Shoichiro, Maruyama, Taro, Shimada, Akira, Nakanishi, Koji, Takahashi, Kazuma, Kobayashi, Tetsuro, Kawabata, Yumiko, Miyashita, Yumi, Kurihara, Susumu, Morita-Ohkubo, Tomoko, Katayama, Shigehiro
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2011; Wiley Subscription Services, Inc
• Subjects: Age of Onset; Asian Continental Ancestry Group - genetics; Autoantibodies - analysis; Autoimmunity; CTLA-4 protein; Diabetes mellitus; Diabetes Mellitus, Type 1 - genetics; Drb1 protein; ErbB-3 protein; Female; Genetic Predisposition to Disease - genetics; genetic susceptibility; Haplotypes; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class II - genetics; HLA-DR Antigens - genetics; HLA-DRB1 Chains - genetics; Humans; Insulin - genetics; Interleukin 2 receptors; Interleukin 7 receptors; Interleukin-2 Receptor alpha Subunit - genetics; Lectins, C-Type - genetics; Male; Monosaccharide Transport Proteins - genetics; Polymorphism, Single Nucleotide; prediction model; Reviews; Single-nucleotide polymorphism; Thyroid; Thyroid Gland - immunology; Tissue typing; type 1 diabetes
• ISSN: 1520-7552; 1520-7560; 1520-7560
• DOI: 10.1002/dmrr.1234

Background We previously reported the associations of human leukocyte antigen (HLA) (DRB1 and DQB1), INS, CTLA4, IL2RA, ERBB3 and CLEC16A with Japanese type 1 diabetes (T1D). In this study, we jointly analysed these loci in addition to IFIH1 and IL7R. Methods A maximum of 790 T1D patients and 953 control subjects were analysed. HLA was determined by sequencing‐based typing. Seven non‐HLA single nucleotide polymorphisms were genotyped using TaqMan assay. Results HLA DRB1*0405, DRB1*0901 and DRB1*0802‐DQB1*0302 haplotypes were positively associated with T1D, while the DRB1*15 haplotypes were negatively associated. Non‐HLA single nucleotide polymorphisms, INS, IL2RA, ERBB3, CLEC16A and IL7R were associated with T1D. By a prediction model using the HLA loci alone (HLA model) or the non‐HLA loci alone (non‐HLA model), it was revealed that the cumulative effect of the non‐HLA model was much weaker than that of the HLA model (average increase in odds ratio: 1.17 versus 3.14). Furthermore, the area under the receiver operating characteristic curve of the non‐HLA model was also much smaller than that of the HLA model (0.65 versus 0.81, p < 10−11). Finally, a patient‐only analysis revealed the susceptible HLA haplotypes and the risk allele of INS to be negatively associated with slower onset of the disease. In addition, the DRB1*0901 haplotype and the risk alleles of ERBB3, CLEC16A and CTLA4 were positively associated with the co‐occurrence of thyroid autoimmunity. Conclusions Although several non‐HLA susceptibility genes in Japanese were confirmed trans‐racially and appear to contribute to the heterogeneity of the clinical phenotypes, the cumulative effect on the ability to predict the development of T1D was weak. Copyright © 2011 John Wiley & Sons, Ltd.