Causal association of genetically predicted 1400 blood metabolites with inflammatory bowel disease risk: A Mendelian...

We utilized an unbiased 2-sample Mendelian randomization approach to investigate the potential causal relationship between 1400 human blood metabolites and the risk of inflammatory bowel disease (IBD). Exposure data were sourced from the largest metabolome-based genome-wide association study (mGWAS), which included 8299 individuals from Canada. The results were primarily derived from a meta-analysis of genome-wide association studies (GWAS) involving 25,042 patients and 34,915 healthy controls, with additional data from a European GWAS database consisting of 12,882 IBD cases and 21,770 healthy controls. The main analysis employed the inverse variance weighted model, alongside Mendelian randomization-Egger regression and the weighted median method for supplementary analysis. Heterogeneity and pleiotropy sensitivity analyses were also conducted to ensure result robustness. The replication analysis of the inverse variance weighted (IVW) method identified 53 blood metabolites significantly associated with IBD risk (P <.05). Following thorough analysis and sensitivity testing, 5 blood metabolites were found to have a significant causal relationship with IBD (P <.05). Specifically, 2 metabolites were linked to an increased risk of IBD: Oleoyl-linoleoyl-glycerol (18:1-18:2) [2] to linoleoyl-arachidonoyl-glycerol (18:2-20:4)[2] ratio (OR = 1.1174, 95% CI = 1.0697-1.1674, P = 6.3693 × 10-7) and N-palmitoyl-heptadecasphingosine (d17:1/16:0) levels (OR = 1.0981, 95% CI = 1.0318-1.1687, P = 3.2196 × 10-3). The other 3 metabolites, including 1-stearoyl-2-arachidonoyl-GPI (18:0/20:4) levels (OR = 0.8864, 95% CI = 0.8375-0.9382, P = 3.1373 × 10-5), 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) levels (OR = 0.8667, 95% CI = 0.8076-0.9301, P = 7.1645 × 10-5), and acetylcarnitine levels (biocrates platform) (OR = 0.8754, 95% CI = 0.8075-0.9490, P = 1.2329 × 10-3), were associated with decreased IBD risk. Notably, no reverse causality was observed for any of these 5 metabolites. In conclusion, 5 blood metabolites were identified as causally associated with IBD, including 2 increasing and 3 decreasing disease risk. These findings can not only provide a new perspective for the pathogenesis of IBD but may also provide a theoretical basis for its prevention and treatment.