Large-Scale Analyses Provide No Evidence for Gene-Gene Interactions Influencing Type 2 Diabetes Risk

Next-Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes


HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow up on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, and β70) that are resistant to T1D among subjects with DQ4-, 5-, 6-, and 7-resistant DQ haplotypes. These 7 residues form 13 common motifs: 6 motifs are significantly resistant, 6 motifs have modest or no associations (P values >0.05), and 1 motif has 7 copies observed among control subjects only. The motifs “DAAFYDG,” “DAAYHDG,” and “DAAYYDR” have significant resistance to T1D (odds ratios [ORs] 0.03, 0.25, and 0.18; P = 6.11 × 10−24, 3.54 × 10−15, and 1.03 × 10−21, respectively). Remarkably, a change of a single residue from the motif “DAAYHDG” to “DAAYHSG” (D to S at β57) alters the resistance potential, from resistant motif (OR 0.15; P = 3.54 × 10−15) to a neutral motif (P = 0.183), the change of which was significant (Fisher P value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, peptide–MHC class II complex stability, β167-169 RGD loop, T-cell receptor binding, formation of homodimer of α-β heterodimers, and cholesterol binding in the cell membrane rafts. Identification of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.


  • § G.K.P. has been retired from Technological Educational Institute (TEI) of Epirus, Arta, Greece since 1 September 2018. The affiliation is given for identification purposes only. As of 1 October 2018, the TEI of Epirus has been absorbed by the University of Ioannina. The respective department is now called Department of Agriculture.

  • This article contains supplementary material online at

  • Received April 14, 2020.
  • Accepted August 24, 2020.

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