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Next generation HLA sequence analysis uncovers seven HLA-DQ amino acid residues and six motifs resistant to childhood type 1 diabetes

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posted on 31.08.2020 by Ada Admin, Lue Ping Zhao, George K Papadopoulos, William W. Kwok, Antonis K. Moustakas, George P. Bondinas, Annelie Carlsson, Helena Elding Larsson, Johnny Ludvigsson, Claude Marcus, Ulf Samuelsson, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark
HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow 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, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif “DAAFYDG”, “DAAYHDG” and “DAAYYDR” have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 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-value = 3.54*10-15) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher’s 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, pMHCII complex stability, b167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications 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.

Funding

The study was supported by a grant (1R56 DK117276) from National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a grant from the European Foundation for the Study of Diabetes (EFSD) Clinical Research Grants Programme 2013 and in part the Swedish Child Diabetes Foundation (Barndiabetesfonden), the National Institutes of Health (DK63861, DK26190), the Swedish Research Council including a Linné grant to Lund University Diabetes Centre, the Skåne County Council for Research and Development as well as the Swedish Association of Local Authorities and Regions (SKL).

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