Leveraging IgG N-glycosylation quantitative-trait loci to characterize the relationship between Type 2 Diabetes and hypertension: A network with bidirectional mendelian randomization study

Background: The relationship between IgG N-glycosylation, type 2 diabetes (T2D) and hypertension is not well understood. Methods: A genome-wide association study (GWAS) of IgG N-glycosylation traits from 536 individuals was performed and 1203 IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) variants targeting 24 IgG N-glycosylation were mapped traits after multi-testing correction. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association between IgG N-glycosylation, T2D and hypertension. Results: By linking IgG N-glycan-QTL variants with GWAS results for T2D and hypertension, 19 putatively causal IgG N-glycans for T2D and 21 putatively causal IgG N-glycans for hypertension were identified. IgG N-glycan-QTL determined IgG N-glycosylation to higher T2D was associated with higher hypertension risk (β [95% CI] =1.234 [0.939-1.529], P <0.001). In addition, IgG N-glycan-QTL determined IgG N-glycosylation to higher hypertension was associated with higher T2D risk (β [95% CI] =0.753 [0.140-1.3669], P =0.016). No evidence of pleiotropic bias was detected in MR-Egger analysis. Conclusions: Overall, our study showed that IgG N-Glycosylation-QTLs determined T2D is associated with higher hypertension risk, and vice versa, performing bidirectional regulation through IgG N-Glycosylation.