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Analysis of the HLA and non‐HLA susceptibility loci in Japanese type 1 diabetes
Author(s) -
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,
MoritaOhkubo Tomoko,
Katayama Shigehiro
Publication year - 2011
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.1234
Subject(s) - human leukocyte antigen , haplotype , single nucleotide polymorphism , allele , genetics , type 1 diabetes , biology , concordance , odds ratio , immunology , genotype , gene , medicine , diabetes mellitus , antigen , endocrinology
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.