Genetic evidence reveals phosphatidylcholine as a mediator in the causal relationship between omega-3 and multiple myeloma risk

Abstract

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.

Keywords: Causal association; Mendelian randomization; Multiple myeloma; Omega-3.

Fig. 1

The overview of the study design and flowchart in this study (by Figdraw). MM, multiple myeloma; SNPs, single nucleotide polymorphisms; LD, linkage disequilibrium; MR, Mendelian randomization; IVW, inverse variance weighted; WM, weighted median; RAPS, robust adjusted profile score; cML, constrained maximum likelihood.

Fig. 2

Two-sample MR forest plots for primary analysis and validation analysis.

Fig. 3

Forest plot of MVMR for omega-3, type 2 diabetes and obesity with risk of multiple myeloma (MM).

Fig. 4

Schematic diagram of mediating effects of phosphatidylcholine (18:2_20:4) levels. β1 represents the causal effect of omega-3 levels on phosphatidylcholine (18:2_20:4); β2 represents the causal effect of phosphatidylcholine (18:2_20:4) on Multiple myeloma (MM); β3 represents the total causal effect of omega-3 on MM. Indirect effect = β1Xβ2. Proportion mediated was the indirect effect divided by the total effect (Proportion mediated = β1Xβ2/β3).