Nature Communications Journal Illustration

Environmental and genetic interaction converges on the Golgi N-glycan branching enzyme Mgat1 and N-glycosylation of CTLA-4 in T cell blasts. Both down- or upregulation of Mgat1 activity decrease branching by limiting N-glycan or UDP-GlcNAc substrate to downstream enzymes, respectively. (1) Soluble receptors associated with the IL2RA*T (rs2104286) and IL7RA*C (rs6897932) MS risk alleles antagonize IL-2 and IL-7 signalling, leading to (2) downregulation of Mgat1, decreased branching and CTLA-4 surface levels and increased MS risk. (3) Vitamin D3 signalling counteracts this by enhancing Mgat1, leading to increased branching, CTLA-4 surface expression and decreased MS risk. (4) The MGAT1 IVAVT–T haplotype (rs7726005, rs2070924, rs2070925) increases Mgat1, which decreases branching, CTLA-4 surface levels and increases MS risk conditional on (5) metabolic production of UDP-GlcNAc. (6) Combining genetic upregulation of Mgat1 by the MGAT1 IVAVT–T haplotype with genetic downregulation of Mgat1 by the IL2RA*T and IL7RA*C MS risk alleles optimizes Mgat1 activity, thereby enhancing branching, CTLA-4 surface expression and mitigating MS risk. The CTLA-4 Thr17Ala (rs231775) variant modifies these interactions by controlling the number of N-glycans attached to CTLA-4, with the Thr17 allele doubling N-glycan number to promote CTLA-4 surface retention and reduce MS risk when combined with MGAT1 IVAVT–T, IL2RA*TT and IL7RA*CC.

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