Abstract
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.