Genetic association between coffee consumption and multiple myeloma mediated by plasma metabolites: a Mendelian randomization study.

Background: Multiple myeloma (MM) is a hematologic malignancy closely associated with diets and metabolic disorders, showing an increasing incidence trend. Genome-wide association studies (GWAS) contribute to exploring the causal relationships between diets, metabolites, and MM, thereby revealing biological mechanisms underlying cancer progression. Methods: This study included large-scale GWAS data for two diets, four metabolomics, and MM. The two-sample Mendelian randomization (MR) analysis was conducted to assess causalities between these dietary patterns, metabolites, and MM. The MR analysis primarily employed the inverse variance weighted (IVW) method, supported by multiple sensitivity analysis and reverse MR analysis to validate significant associations. Mediation analysis identified specific metabolites mediating the causal relationships between diets and MM. Results: Univariate MR analysis suggested that coffee consumption (ORIVW = 2.72; 95% CI: 1.21-6.10; PIVW = 0.015, P_fdr = 0.022), decaffeinated coffee consumption (ORIVW = 7.10; 95% CI: 1.33-37.87; PIVW = 0.022, P_fdr = 0.022), ground coffee consumption (ORIVW = 4.04; 95% CI: 1.25-13.02; PIVW = 0.019, P_fdr = 0.022), instant coffee consumption (ORIVW = 6.13; 95% CI: 1.95-19.34; PIVW = 0.002, P_fdr = 0.008), and coffee max liking (ORIVW = 2.94; 95% CI: 1.23-7.03; PIVW = 0.015, P_fdr = 0.035) were associated with increased MM risk. Metabolomic MR analysis identified 19 plasma metabolites, 1 blood and urine biomarker, and 4 plasma lipids with significant association with MM. Mediation analysis indicated that hippurate and cinnamoylglycine mediated 35.55% (P < 0.001) and 21.85% (P = 0.002) of the genetically predicted effect of coffee consumption on MM risk, respectively. Cinnamoylglycine contributed 12.63% (P = 0.042) to the total causal effect of ground coffee consumption on MM. Hippurate (21.43%, P < 0.001), 3-hydroxyhippurate (4.39%, P = 0.031), and cinnamoylglycine (8.79%, P = 0.010) mediated the genetically predicted impact of instant coffee consumption on MM risk. Metabolic pathway analysis suggested that glutathione metabolism significantly contributes to MM pathogenesis (P = 0.002, FDR < 0.05). Conclusions: Our findings support the adverse causal effects of various coffee consumption on MM risk, identifying hippurate, 3-hydroxyhippurate, and cinnamoylglycine as key mediators, driving the relationship potentially through the glutathione metabolism pathway.