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

作者：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

来源：Diabetes/Metabolism Research and Reviews, 2011, 27(8): 844-848.

DOI：10.1002/dmrr.1234

• type 1 diabetes
• genetic susceptibility
• prediction model
• single nucleotide polymorphism

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.

• 出版日期2011-11
• 单位河北医科大学