Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here... Show moreGlycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets. Show less
With the picolinyl (Pic) group as a C‐1 located directing group and N3 as versatile precursor for C5‐NH2, a novel 1‐Pic‐5‐N3 thiosialyl donor was designed and synthesized, based on which a new... Show moreWith the picolinyl (Pic) group as a C‐1 located directing group and N3 as versatile precursor for C5‐NH2, a novel 1‐Pic‐5‐N3 thiosialyl donor was designed and synthesized, based on which a new sialylation protocol was established. In comparison to conventional sialylation methods, the new protocol exhibited obvious advantages, including excellent α‐stereoselectivity in the absence of a solvent effect, broad substrate scope encompassing the challenging sialyl 8‐ and 9‐hydroxy groups of sialic acid acceptors, flexibility in sialoside derivative synthesis, high temperature tolerance and easy scalability. In particular, the applicability to the synthesis of complex and bioactive N‐glycan antennae when combined with the MPEP glycosylation protocol via the “latent‐active” strategy has been shown. Mechanistically, the excellent α‐stereoselectivity of the novel sialylation protocol could be attributed to the dramatic electron‐withdrawing effect of the protonated Pic groups, which was supported by control reactions and DFT calculations. Show less
With the picolinyl (Pic) group as a C‐1 located directing group and N3 as versatile precursor for C5‐NH2, a novel 1‐Pic‐5‐N3 thiosialyl donor was designed and synthesized, based on which a new... Show moreWith the picolinyl (Pic) group as a C‐1 located directing group and N3 as versatile precursor for C5‐NH2, a novel 1‐Pic‐5‐N3 thiosialyl donor was designed and synthesized, based on which a new sialylation protocol was established. In comparison to conventional sialylation methods, the new protocol exhibited obvious advantages, including excellent α‐stereoselectivity in the absence of a solvent effect, broad substrate scope encompassing the challenging sialyl 8‐ and 9‐hydroxy groups of sialic acid acceptors, flexibility in sialoside derivative synthesis, high temperature tolerance and easy scalability. In particular, the applicability to the synthesis of complex and bioactive N‐glycan antennae when combined with the MPEP glycosylation protocol via the “latent‐active” strategy has been shown. Mechanistically, the excellent α‐stereoselectivity of the novel sialylation protocol could be attributed to the dramatic electron‐withdrawing effect of the protonated Pic groups, which was supported by control reactions and DFT calculations. Show less
