IgG N-glycosylation in the causal associations between adiposity, tobacco use, and the risk of cardiovascular diseases: A mediation Mendelian randomization study.

BACKGROUND: Despite interest in the health effects of IgG N-glycosylation, the mediating role of IgG N-glycosylation in the effects of adiposity and tobacco use on cardiovascular diseases (CVDs) has not been systematically studied. OBJECTIVE: This study aimed to investigate the causal effects of adiposity and tobacco use on CVDs and the potential mediating role of 23 traits of IgG N-glycosylation using Mendelian randomization (MR). METHODS: Summary statistics from GWAS were used. Two-sample MR assessed the causal links between adiposity, tobacco use, and CVDs, while two-step MR examined whether IgG N-glycosylation traits mediate these associations. Random-effects inverse-variance weighted analyses, along with MR-Egger, weighted median, simple, and weighted model approaches, were conducted. RESULTS: We observed genetically predicted body mass index (OR = 1.48, 95% CI: 1.40, 1.56), fat mass index (OR = 1.68, 95% CI: 1.37, 2.06), fat-free mass index (OR = 1.55, 95% CI: 1.27, 1.89), lifetime smoking index (OR = 1.75, 95% CI: 1.43, 2.14), and smoking initiation (OR = 1.15, 95% CI: 1.06, 1.25) were positively associated with CVDs. Moreover, IGP5 mediated 5.4% of the effect of BMI on pulmonary embolism, whereas IGP7 mediated 2.8% of the effect of BMI on coronary artery disease. CONCLUSION: Our findings illustrated the causal associations of adiposity and tobacco use with CVDs, with IgG N-glycosylation traits potentially acting as mediators, and thereby highlighting possible mechanistic targets for further investigation.