Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

Abstract

Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(a1, b1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of transencoded HLA DQ molecules in the determination of HLA-associated risk in T1D.

Epistasis amongHLA-DRB1, HLA-DQA1,andHLA-DQB1loci determines multiple sclerosis susceptibility

“…Observed cis interactions between HLA-DRB1*15 and HLA-DQA1*0102 and between HLA-DRB1*15 and HLA-DQB1*0602 may reflect either functional relationships between these alleles or additional haplotype-specific effects. The availability of a large (32) and diabetes (33) and functional epistasis between HLA-DRB1 and HLA-DRB5 has been demonstrated in murine models of MS (3). In addition to the allelic interactions reported here, the differential susceptibility associated with different HLA-DRB1*15-bearing haplotypes (11) may imply structural and epigenetic influences.…”

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

“…It has been suggested by geneticepidemiological studies that the DQA1*0501-DQB1*0302 trans-dimer is responsible for the increased odds ratio in heterozygous individuals. 12,13 Intriguingly, as DQ6/8 trans-dimer formation is not possible, DQ6/8 heterozygous individuals only express the respective cis-dimers. 14,15 Biopsies taken from newly diagnosed patients to obtain autoreactive T cells from the proximal pancreatic lymph nodes are a rarity, and little is known of insulinspecific T cells in human beings.…”

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

“…Nevertheless, studies on type 1 diabetes indicate that trans-encoded HLA molecules may play a role in pathogenesis (8). It has been observed that individuals who are heterozygous for DQ2.5 (DQA1*05: 01/DQB1*02:01) and DQ8 (DQA1*03:01/DQB1*03:02) are susceptible to type 1 diabetes with an almost 5-fold higher risk than those who are homozygous for either of the DQ variants (1,9,10). 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).…”