We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes.
Analysis of T1D-associated alleles at other HLA loci (HLA-A, HLA-B, and HLA-DPB1) on DRB1*03:01 haplotypes suggests that DRB3*02:02 on the DRB1*03:01 haplotype can contribute to T1D risk.
These associations indicate that the B 39 alleles significantly increase risk when present on specific HLA-DR/DQ haplotypes, and HLA-B typing in concert with specific HLA-DR/DQ genotypes should facilitate genetic prediction of type 1 diabetes, particularly in a research setting.
The aim of our study was to test the association of the polymorphism of the MIC-A gene with Type I (insulin-dependent) diabetes mellitus and evaluate the interaction between MIC-A and TNFA, HLA-B, HLA-DR and HLA-DQ gene polymorphism.
Besides the acknowledged correlation between the HLA-A*02 and HLA-B*15 alleles (as well as low birth weight) and type I diabetes and between the HLA-B*38 and HLA-DRB1*13 alleles (as well as high birth weight) and several autoimmune diseases, we cannot predict if our babies, healthy at birth, will suffer from these pathologies during life.
A study of 12 families in which BF*F1 was segregating suggested that BF*F1 and HLAB*18 are components of a haplotype associated with Type 1 diabetes in this population and that both haplotypes of an affected parent may contribute to the development of Type 1 diabetes.
Since, in the early 1970s, research by Nerup's and Cudworth's groups revealed associations between the HLA-B locus and IDDM, the HLA markers are considered the classical genetic markers for IDDM susceptibility.
The independent predisposing effect of the HLA-B*39:06 allele with type 1 diabetes was confirmed in the Finnish population but the association of the A*24:02 and B*39:01 alleles remained inconclusive whilst both A*24:02 and B*39:01 affected the progression rate from seroconversion to autoantibody positivity to overt type 1 diabetes.
Because reduced thymic insulin expression is associated with impaired immunological tolerance to insulin and increased T1D risk in patients, we incorporated this in our model as well, finding that HLA-B*39:06-transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset and a higher overall prevalence as compared with littermates with typical thymic insulin expression.
Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain-related protein A (MICA; located between TNFA and HLA-B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease.
Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM.
The risk for type 1 diabetes conferred by certain DR/DQ haplotypes is modified by the presence of the HLA-B*39 and this confirms the independent disease predisposing effect of the HLA-B*39 allele.
HLA-B (n=395), HLA-DRB1 (n=501) and HLA-DQB1 (n=475) alleles were genotyped in pregnant women (mothers of children who later developed type 1 diabetes and mothers of non-diabetic children).
The localisation of tumour necrosis factor genes on the short arm of chromosome 6 between HLA-B and the complement genes (Class III) prompted us to investigate a possible polymorphism of TNF-alpha at the genomic level in relation to Type 1 diabetes susceptibility.
Although MHC class II genes have a stronger association with type 1 diabetes than MHC class I genes, studies have shown that MHC class I molecules play an independent role in the etiology of type 1 diabetes, and the existence of susceptibility genes within a segment of MHC between the HLA-B and TNF genes has been predicted, where MHC class I chain-related gene A (MICA) resides.
Because HLA-B and DRB1 genes were independently associated, both of these genes may be contributed primarily to the pathogenesis of type 1 diabetes in Japanese.
Unlike <i>HLA-B*18</i> or <i>-B*39</i>, <i>HLA-A*24</i> was associated with delayed progression from single- to multiple-autoantibody positivity (<i>P</i> = 0.009) but not to type 1 diabetes.