A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles.

Abstract

HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allelespecific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, DwlO, Dwl3, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and DwlO, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR < 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination ofcertain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQa). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/IDQ3.2, Dw41 or DR3/[DQ3.2, DwlOj had a relative risk of 38.0 and an absolute risk of I in 15.

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

“…Altogether, the current results integrate well with evidence and speculations pointing to a broad and nonspecific immunopathogenic effect of DR3, 20,30,31 an association of DR3 with islet autoantibody-positivity with or without progression to diabetes, 32 independent associations of DR4 and DQ8 with type 1 diabetes 33 and a delayed effect of DQ that may accelerate or hinder the progression of b-cell destruction and dysfunction. 12,[34][35][36] We previously reported significant clustering and coclustering of islet and celiac autoimmunity in the kindred, explained in part by a common association with DR3-DQ2, which was present in all of 16 relatives with celiac autoimmunity.…”

Genetics of type 1 diabetes mellitus

“…53,54 It has been more difficult to ascertain the roles of separate HLA-DR genes. 45,55 Analysis of the linkage between HLA-DQ and DR alleles on DQ8-haplotypes, demonstrated that the frequencies of only certain HLA-DR4-associated DRB1 alleles are increased among T1D patients. 55 This has since been confirmed in larger studies by other groups.…”

Genetic linkage and association studies of Type I diabetes: challenges and rewards

“…Similarly, several HLA haplotypes positively associated with Type I diabetes (including DR4-DQB1*0302) were found to encode an amino acid other than aspartate at position 57 of the DQB1 chain, again implying that DQB1 was the primary susceptibility locus [52]. However, an elegant study showed that DR4 haplotypes encoding both DRB*0401 (a subtype of DR4) and DQB*0302 were more diabetogenic than DR4 haplotypes encoding only one of these [53] ± thus, DRB1 and DQB1 together could confer susceptibility. The HLA-DQA1 locus also appears to be involved in susceptibility [54,55].…”