The Effect of HLA-B Allele on the IDDM Risk Defined by DRB1*04 Subtypes and DQB1*0302

Abstract

The genes encoding the HLA-DQ heterodimer molecules, DQB1 and DQA1, have been found to have the strongest association with IDDM risk, although there is cumulative evidence for the effect of other gene loci within the major histocompatibility complex gene region. After the HLA-DQ locus, the HLA-DR locus has been suggested most often as contributing to the disease susceptibility. In this study we analyzed at the population level the effect of DR4 subtypes and class I, HLA-B alleles, on IDDM risk when the influence of the DQ locus was stratified. In all three populations studied (Estonian, Latvian, and Russian), DQB1*0302 haplotypes most frequently carried DRB1*0401 or DRB1*0404. DRB1*0401 was the most prevalent subtype in IDDM patients, whereas DRB1*0404 was decreased in frequency. DRB1*0402 was also prevalent among Russian haplotypes, but was not associated with IDDM risk. When HLA-B alleles were analyzed, strong associations between the presence of specific B alleles and DRB1*04 subtypes were detected. The HLA-B39 allele was found significantly more often in DRB1*0404-DQB1*0302-positive patients than in healthy control subjects positive for this haplotype: 27 of 54 (50%) vs. 4 of 49 (8.2%) (P < 0.0001). The results demonstrate that DQ and DR genes cannot explain all of the HLA-linked susceptibility to IDDM, and that the existence of a susceptibility locus telomeric to DR is probable.

Effect of HLA Class I and Class II Alleles on Progression From Autoantibody Positivity to Overt Type 1 Diabetes in Children With Risk-Associated Class II Genotypes

“…The major finding in our study—the strong effect of B*39 on the progression from β-cell autoimmunity to clinical disease—was only seen in subjects carrying the combination of both major class II risk haplotypes, the DR3/DR4 genotype. We have earlier observed HLA-B*39 to be common in type 1 diabetes–associated DRB1*0404 haplotypes in Finland (5), and we have also been able to demonstrate its predisposing effect on type 1 diabetes risk in DRB1*0404-DQB1*0302–positive subjects in Estonia and Russia (18). The presence of the HLA-B*39 allele in the DRB1*08-DQB1*0402 haplotype has also been found to be a risk factor for type 1 diabetes (3).…”

Population‐based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA‐DQB1, HLA‐DQA1 and HLA‐DRB1 loci

“…DRB1*0405 was shown to be the strongest DR4 subtype conferring risk for Type 1 diabetes in several populations including African-Americans and Mexican-Americans, Caucasian French and Sardinians [29], while it was not present in the Finnish population [13]. Such differences mostly mirror the prevalence of risk alleles in the background populations, but may also re¯ect haplotypic associations and/or yet uncharacterized susceptibility genes within the HLA gene region [16,30]. Such differences mostly mirror the prevalence of risk alleles in the background populations, but may also re¯ect haplotypic associations and/or yet uncharacterized susceptibility genes within the HLA gene region [16,30].…”

“…Standard dot-blot hybridization with digoxygeninlabelled oligonucleotide probes was used as a reference method [16]. Standard dot-blot hybridization with digoxygeninlabelled oligonucleotide probes was used as a reference method [16].…”

Use of Nonobese Diabetic Mice to Understand Human Type 1 Diabetes

“…Likewise, susceptibility has also been linked to specific HLA-A and HLA-B Class I alleles (29), however little is known about the role of the disease-associated variants in T1D. However, it should be noted that when HLA-B*39 is combined in a HLA haplotype with DRB1*0404-DQB1*0302, patients are at significantly heightened risk (30). This is a demonstration of gene-gene interaction or epistasis, controlling T1D onset.…”