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

Genes Immun. 2004 Aug;5(5):381-8. doi: 10.1038/sj.gene.6364106.

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(alpha 1, beta 1) 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 trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / ethnology
  • Diabetes Mellitus, Type 1 / genetics*
  • Dimerization
  • Epistasis, Genetic*
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • HLA-DQ Antigens / genetics*
  • HLA-DQ Antigens / metabolism
  • HLA-DQ beta-Chains
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / metabolism
  • HLA-DRB1 Chains
  • Haplotypes / genetics
  • Humans
  • Male
  • Risk

Substances

  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen