Background: Previous observational studies have suggested a potential association between Epstein-Barr virus (EBV) infection and the development of multiple myeloma (MM), but this relationship is not clear. Therefore, we conducted a systematic Mendelian randomization (MR) analysis to investigate the causal relationship between EBV infection and the risk of MM, while exploring the possible mediating role of immune cells in this association. Methods: The study first conducted a two-sample MR analysis using the MM R11 dataset from the FinnGen Consortium to evaluate the causal relationship between five EBV infection-related antibodies (AEB-IgG, EA-D, EBNA-1, VCA-p18, and ZEBRA) and MM, with validation in the MM R10 dataset. A reverse MR analysis was then performed. For significant results, multivariable MR (MVMR) was used to adjust for the effects of confounding risk factors. Next, a two-step MR mediation analysis was applied to investigate the potential mediating role of 731 immune cell types between positive exposure and MM. Multiple sensitivity analyses were conducted to assess the robustness of the findings. Results: A two-sample MR study found that EBNA-1 antibodies (OR = 1.36, 95% CI: 1.06–1.73; P = 0.015) were associated with an increased risk of MM, with similar results observed in the FinnGen Consortium R10 replication study. Although the association did not remain statistically significant after false discovery rate (FDR) adjustment (P_fdr = 0.075), further adjustment for relevant confounders using multivariable MR (MVMR) demonstrated that EBNA-1 antibodies (OR = 1.33, 95% CI: 1.01–1.75; P = 0.041) were still significantly associated with an increased risk of MM. Reverse MR analysis indicated no causal effect of MM on EBV-related antibodies. A two-sample MR analysis involving 731 immune cell phenotypes identified 27 potential mediating cell types. Ultimately, two-step MR confirmed that HLA-DR on myeloid dendritic cells (HLA-DR⁺ mDC) serves as a mediating factor, with EBNA-1 antibodies downregulating HLA-DR⁺ mDC, thereby increasing MM risk. Multiple sensitivity analyses supported the robustness of these findings. Conclusion: The findings of this study suggest that EBNA-1 antibodies may increase the risk of MM by downregulating HLA-DR⁺ mDC. This indicates that chronic EBV infection may contribute to an elevated risk of MM. We hope these results provide new insights for future research on the prevention and treatment of MM.

Previous observational studies have indicated that omega-3 may reduce the risk of various cancers. However, the relationship between omega-3 and the incidence of multiple myeloma (MM) remains unclear. Therefore, we conducted a systematic Mendelian randomization (MR) analysis to investigate the causal relationship between omega-3 and the risk of developing MM, while also exploring the potential mediating role of plasma lipids in this association. First, we conducted a two-sample MR study with MM using the omega-3 GWAS data from Richardson TG. We then repeated the validation with the other three omega-3 GWAS data and performed a meta-analysis of the MR results for a total of four omega-3 data. In the second step, we used multivariate Mendelian randomization (MVMR) analyses to adjust for the effects of confounders and explore the direct causal effects of omega-3 with MM. In the third step, we employed a two-step MR to investigate the potential mediating roles of 179 plasma lipids in the association between omega-3 and the risk of MM. Multiple sensitivity analyses were used to assess the robustness of the results. A two-sample MR analysis found that omega-3 can reduce the risk of MM (OR = 0.80, 95% CI 0.69-0.94; P = 0.005). In subsequent validation, omega-3 data from both Kettunen J and Davyson E yielded similar results. However, data from Zhang S indicated that omega-3 was not associated with MM risk. Ultimately, the meta-analysis results demonstrated that omega-3 can lower the risk of MM (OR = 0.80, 95% CI 0.72-0.88; P < 0.001). Furthermore, MVMR analysis, after adjusting for relevant risk factors such as obesity and type 2 diabetes, confirmed that omega-3 still reduces the risk of MM. Finally, two-step MR identified phosphatidylcholine (18:2_20:4) as a potential mediator of the causal relationship between omega-3 and MM. Various sensitivity analyses validated the robustness of these findings. Our study suggests that omega-3 may reduce the incidence risk of MM by increasing the levels of phosphatidylcholine (18:2_20:4). We hope that these findings will provide new insights for the prevention and treatment of MM.