title: Analysis of the HLA and non-HLA susceptibility loci in Japanese type 1 diabetes.
abstract: 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.
authors: Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
authors: Hisakuni
authors: H
authors: Yamashita
authors: Takuya
authors: T
authors: Awata
authors: Eiji
authors: E
authors: Kawasaki
authors: Hiroshi
authors: H
authors: Ikegami
authors: Shoichiro
authors: S
authors: Tanaka
authors: Taro
authors: T
authors: Maruyama
authors: Akira
authors: A
authors: Shimada
authors: Koji
authors: K
authors: Nakanishi
authors: Kazuma
authors: K
authors: Takahashi
authors: Tetsuro
authors: T
authors: Kobayashi
authors: Yumiko
authors: Y
authors: Kawabata
authors: Yumi
authors: Y
authors: Miyashita
authors: Susumu
authors: S
authors: Kurihara
authors: Tomoko
authors: T
authors: Morita-Ohkubo
authors: Shigehiro
authors: S
authors: Katayama
mesh_terms: D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D001323:Autoantibodies / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013961:Thyroid Gland / Q000276:immunology
chemical_list: D001323:Autoantibodies; C522505:CLEC16A protein, human; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C508017:IL2RA protein, human; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins