Particular HLA-DQ alpha beta heterodimer associated with IDDM susceptibility in both DR4-DQw4 Japanese and DR4-DQw8/DRw8-DQw4 whites.

Insulin-dependent diabetes mellitus (IDDM) susceptibility is associated with the DR4-DQw4 haplotype in Japanese and the DR4-DQw8/-Drw8-DQw4 genotype (among others) in whites. We investigated whether these Japanese and white individuals encode the same or a similar DQ alpha beta heterodimer, which may be an IDDM-susceptibility molecule in both populations. First, we carried out genomic DQA1 and DQB1 typing with sequence-specific oligonucleotide probes. The results revealed that Japanese DR4-DQw4 and white DR4-DQw8/DRw8-DQw4 IDDM patients carried the DQA1*0301 allele and the DQB1*0401 or DQB1*0402 allele, either in the cis (Japanese DR4-DQw4 individuals) or trans (white DR4-DQw8/DRw8-DQw4 individuals) position. Because the DQB1*0401 and DQB1*0402 alleles differ only at residue 23, these DQB1 genes are very similar. We next tested cells from these individuals with a particular DQ-specific T-lymphocyte clone, HH58. The clone was only restimulated with cells from Japanese individuals who carried the DQA1*0301 and DQB1*0401 alleles in the cis position or white individuals who carried the DQA1*0301 and DQB1*0402 alleles in the trans position. Thus, particular cis- or trans-encoded DQ alpha beta heterodimers, which in both cases are recognized by T lymphocytes, may confer susceptibility to IDDM in both ethnic groups.

Novel HLA-DR2 and -DR3 haplotypes among Norwegian Caucasians.

In the Northern European population, all DR2 haplotypes encoded by DRB1*1501 have previously been found to carry the DQA1*0102 and DQB1*0602 alleles, and DR3 haplotypes have been found to carry the DQA1*0501 and DQB1*0201 alleles. Here we report a novel recombinant DR2 haplotype carrying the DRB1*1501, DQA1*0102 and DQB1*0603 alleles as well as a novel recombinant DR3 haplotype carrying the DRB1*0301, DRB3*0101, DQA1*0102 and DQB1*0602 alleles.

Distribution of HLA-DRB1, -DQA1 and -DQB1 alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus.

We have studied 87 unrelated Caucasian insulin-dependent diabetes mellitus (IDDM) patients and 181 healthy controls by oligotyping for 20 DRB1, eight DQA1 and 13 DQB1 alleles, and established their DR-DQ haplotypes and DQ genotypes. An increase of DRB1 alleles encoding DR4 was found among IDDM patients, but the distribution of DR4 subtypes did not differ among DR4-positive IDDM patients and controls. The frequency of certain DRB1-DQA1-DQB1 haplotypes and DQA1-DQB1 genotypes was significantly increased among IDDM patients. Taken together, the data suggest that IDDM is primarily associated with several (at least five) different DQ alpha beta heterodimers.

Distribution of HLA class II alleles among Norwegian Caucasians.

We report genomic HLA class II typing of 181 randomly selected Norwegian controls. Seventeen DRB1, 7 DQA1, 10 DQB1, 2 DPA1, and 16 DPB1 alleles were found in the tested population. HLA class II antigen and allele frequencies are given, as well as the distribution of DRB1, DQA1, DQB1 haplotypes. Linkage disequilibrium between some DPB1 alleles and DRB1 and/or DQB1 alleles are also reported.

Rheumatoid arthritis may be primarily associated with HLA-DR4 molecules sharing a particular sequence at residues 67-74.

Genomic typing of in vitro amplified DNA with sequence-specific oligonucleotide (SSO) probes was performed for DRB1, DQA1, DQB1, DPA1 and DPB1 alleles in 54 random Norwegian rheumatoid arthritis (RA) patients and 181 healthy controls. DRB1 alleles encoding the serological specificity DR4 were found in 80% of the patients, compared to 34% of the controls (relative risk = 7.9, p less than 0.0001). All DR4-positive RA patients carried either DRB1*0401 (Dw4), 0404 (Dw14), or 0405 (Dw15), while no patients were found to carry DRB1*0402 (Dw10) or 0403 (Dw13). The frequency of the DRB1*0101 allele encoding DR1 was not increased, even among DR4-negative RA patients, and we were unable to detect any sharing of other class II alleles among DR4-negative patients. No contribution of any DQA1, DQB1, DPA1 or DPB1 alleles to RA susceptibility could be detected. The results suggest that in the Norwegian population RA is primarily associated with a shared sequence at residues 67-74 of the DR beta 1 chain, but only when this sequence is expressed on DR4 molecules.

The amino acid at position 57 of the HLA-DQ beta chain and susceptibility to develop insulin-dependent diabetes mellitus.

In Caucasoids HLA-DQB1 genes encoding amino acids other than aspartic acid at position 57 of the DQ beta chain (non-Asp-57) are associated with susceptibility to develop insulin-dependent diabetes mellitus (IDDM), while resistance is associated with aspartic acid at this residue (Asp-57). Following amplification of genomic DNA by the polymerase chain reaction, the DQB1 alleles of 87 random Norwegian IDDM patients and 187 healthy controls were investigated with 11 different sequence-specific oligonucleotide probes. Of these patients 82% carried DQB1 alleles encoding non-Asp-57 at both of their DQ beta chains, compared to 27% of the controls (relative risk = 12.2, p less than 0.0001). Sixteen percent of the patients (versus 51% of the controls) were heterozygous Asp-57/non-Asp-57. Two percent of the patients (22% of the controls) were apparently Asp-57 homozygous. The results demonstrate that non-Asp-57 DQ beta chains are associated with susceptibility to develop IDDM but also indicate that the protection associated with DQ beta Asp-57 may not be as dominant as reported by others.

An increased risk of insulin-dependent diabetes mellitus (IDDM) among HLA-DR4,DQw8/DRw8,DQw4 heterozygotes.

Serological HLA typing of 92 insulin-dependent diabetes mellitus (IDDM) patients and 300 healthy controls was performed by the immunomagnetic typing technique. We found an increased risk of IDDM among DR4/w8 heterozygotes, similar to that seen for DR3/4 heterozygotes. The DQ alleles of these DR4/w8 patients were therefore established. When hybridized with a cDNA DQB probe, BamHI-digested DNA from eight out of the nine DR4/w8 patients revealed only one single 10.8-kb DQB1-specific fragment typical of DQw4 and DQw8. DNA from all DR4/w8 patients also hybridized to an oligonucleotide probe corresponding to amino acids (aa) 23-30 of the beta chain of DQw8. However, using the oligonucleotide probe, the staining intensity was found to be only half of that seen when DNA from DQw8 homozygotes was used instead, suggesting that the eight DR4/w8 patients had DQw8 in a single dose and carried the DQw4 allele at the DRw8 haplotype. Therefore, eight of nine DR4/w8 IDDM patients seemed to be DR4,DQw8/DRw8,DQw4, which, thus, may be associated with susceptibility to develop IDDM. One common explanation of IDDM susceptibility for DR4,DQw8/DRw8,DQw4 and DR3,DQw2/DR4,DQw8 heterozygotes may be that they share similar DQ alpha beta epitopes encoded by DQA and DQB genes in trans.