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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 2020-08-31, 18:19 authored by Ada AdminAda 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 LernmarkHLA-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.