Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B.

Abstract

Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)-and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association. Diabetes 49:2217-2221, 2000 H LA localization of the genes predisposing to type 1 diabetes is well established. DQB1, DQA1, and DRB1 genes are considered primary and major loci associated with type 1 diabetes. However, evidence is accumulating that the HLA class I-III region contains gene(s) associated with an increased risk for type 1 diabetes (1-4) or its earlier age at onset (5-8). We searched for an additional HLA gene associated with type 1 diabetes among Finnish patients and control subjects stratified for the DQ-DR alleles.Initially, samples from >1,400 type 1 diabetic patients and >30,000 control subjects were collected and genotyped for DQB1 (9). DQB1*02/0302 subjects were then studied for the DQA1*05 and *0201 alleles and DR4 subtypes (of which only DRB1*0401 and DRB1*0404 are frequent among Finns). Thus, a group stratified for the DQA1*05-DQB1*02/ DQB1*0302-DRB1*0404 [DR3/4(0404)] genotype (75 patients and 181 control subjects) and a group stratified for the DQA1*05-DQB1*02/DQB1*0302-DRB1*0401 [DR3/4(0401)] genotype (241 patients and 354 control subjects) were selected. These subjects are all DR3/DR4 haplotype heterozygotes: one group carries DR404 and the other DR401 haplotype. Thus, within each group we excluded the diabetogenic effect of the known DQ-DR markers.In these groups, selected alleles of the HLA-B and HLA-A genes and 10 microsatellites (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) were studied to map a non-class II HLA gene associated with type 1 diabetes susceptibility. These cover distance of ~2,300 kb and include the whole HLA class I region and the class I-III boundary (Fig. 1).We found that in the DR3/404-and DR3/401-stratified groups there was only one allele at each microsatellit...

Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

“…However, this model has not explained why HLA-DRB1*0404 is not consistently associated with T1DM 3 (Table 1), since this allele invariably occurs with DQB1*0302. Undlien et al 3 suggested that DRB1*0404 confers resistance that counteracts the diabetogenic effect 15 Here we showed that carriage of C4B3 and HLA-B15 significantly enhanced the risk of diabetes in carriers of HLA-DRB1*0401; (Tables 1 and 3). While we did not eliminate a role for HLA-DQB1*0302, a gene in the central MHC would explain our data.…”

Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

“…Allele 2 at this locus, located in the class III region, is positively associated with disease, again on the DQ2-DR3 haplotype, but independently of DQ2-DR3 itself. Similarly, in a Finnish study 9 an island of association with T1D, associated with DQ8-DR4 haplotypes but independent of the DQ8 or DR4 alleles themselves, was reported. The authors suggested that a disease locus could be mapped to a 240 kb region encompassing HLA-B.…”

“…41 In addition, it is possible that the same single locus in the class II-centromeric class I region also explains the heterogeneity in risk reported for DQ8-DRB1*0404 haplotypes in Finland. 7,9 Zavattari et al 10 suggested that three markers, DMB, DOB and TNFc, were independently associated with T1D, but these data could be explained by a single extended susceptibility haplotype. Nonetheless, Sardinian haplotypes differ significantly centromeric of DQB1, and a third non-DQ/DR variant reducing the DQ2-DR3 haplotype susceptibility in this population is a possibility.…”

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…9 Furthermore, it indicates that our susceptibility locus maps away from the classical MHC, although additional risk loci are also believed to exist there, in particular for HLA-B. 25,[27][28][29] It is interesting to note that conditional logistic regression analyses in the T1DGC dataset showed that the associations with the PRSS16 SNPs and one of the BTN SNPs were independent of HLA-B, and also of the other class I loci. The associations with the PRSS16 SNPs also seemed independent of the earlier reported UBD and HLA-G associations, though some dependency was seen in the regression analyses between one of the HLA-G SNPs and one of the PRSS16 SNPs, even though there was hardly any LD between these SNPs when calculated on the basis of the entire T1DGC dataset.…”