The role of immune cells in multiple myeloma: a bidirectional Mendelian randomization study

Prior research has highlighted immune cells' critical role in multiple myeloma (MM) pathogenesis, yet the causal relationships between them have remained obscure.

We utilized data from genome-wide association studies (GWAS) of European cohorts to conduct a Mendelian Randomization (MR) analysis, aiming to establish causal links between immune cell phenotypes and MM. We selected single nucleotide polymorphisms (SNPs) associated with immune cell traits at a suggestive significance threshold (P < 1 × 10^-5) to ensure sufficient instrumental variables, with F-statistics (>10) calculated to assess instrument strength. Multiple MR methods were applied to 731 immune phenotypes and MM.

Eight immunophenotypes showed nominal associations with MM risk (P < 0.05). However, no associations survived the strict Bonferroni correction for multiple testing. Suggestive causal effects of MM on immunophenotypic traits are predominantly negative, implying that MM may impair the functionality of immune cells.

This study uses GWAS data to elucidate the genetic impact of immune cells on the initiation and progression of MM. It presents genetic evidence suggesting that immune cells could alter MM risk based on a thorough genetic analysis. Bidirectional two-sample MR identified eight distinct immunophenotypes (encompassing four immune signatures: MFI, RC, AC, MP) with causal effects on MM.

Our study provides preliminary evidence for potential causal links between specific immune traits and MM risk. Independent replication in larger cohorts and functional validation are warranted given the nominal significance of these associations, which may inform future immunotherapeutic investigations. These findings contribute to a better understanding of the complex immune - MM interplay and may guide future investigations into immunotherapeutic approaches.