Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping

Abstract

INSULIN-dependent (type I) diabetes mellitus (IDDM) follows an autoimmune destruction of the insulin-producing beta-cells of the pancreas. Family and population studies indicate that predisposition is probably polygenic. At least one susceptibility gene lies within the major histocompatibility complex and is closely linked to the genes encoding the class II antigens, HLA-DR and HLA-DQ (refs 3, 4). Fine mapping of susceptibility genes by linkage analysis in families is not feasible because of infrequent recombination (linkage disequilibrium) between the DR and DQ genes. Recombination events in the past, however, have occurred and generated distinct DR-DQ haplotypes, whose frequencies vary between races. DNA sequencing and oligonucleotide dot-blot analysis of class II genes from two race-specific haplotypes indicate that susceptibility to IDDM is closely linked to the DQA1 locus and suggest that both the DQB1 (ref. 7) and DQA1 genes contribute to disease predisposition.

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

“…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]. In addition to susceptibility alleles, there are also protective alleles.…”

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

“…In the absence of complete genotyping of all genes in the relevant regions and data from functional studies of candidate polymorphisms in these islands, haplotype mapping may help locate additional aetiological variants. 6,[14][15][16] This method relies on identifying recombination break points and blocks of LD and then measuring the disease association of the blocks, or ancestral haplotype segments.…”

Structural and Functional Studies of trans-Encoded HLA-DQ2.3 (DQA1*03:01/DQB1*02:01) Protein Molecule

“…This phenomenon can be explained by the formation of trans-encoded molecules DQ8.5 (DQA1*05:01/DQB1*03:02) and DQ2.3 (DQA1*03:01/DQB1*02:01), which could present one or a few specific diabetogenic epitopes to CD4 ϩ T-cells, possibly inducing an immune response that leads to destruc-tion of insulin-producing pancreatic ␤-islet cells (8). A strong argument for involvement of the DQ2.3 heterodimer in type 1 diabetes comes from trans-racial gene mapping studies that have found that this heterodimer, which is typically found in the trans-configuration among Caucasian subjects, exists and is overrepresented in the cis-configuration among type 1 diabetes patients of African origin (11,12). The increased diabetes risk of the African DQ2.3 (DQA1*03:01/DQB1*02) carrying DR7 haplotype is contrasted by a protecting effect of the DQ2.2 (DQA1*03:01/DQB1*02) carrying DR7 haplotype of European origin, speaking to the functional importance of ␣-chain in the DQ2.3 molecule (12).…”