Work

Causal pathways in Lymphoma: The role of serum metabolites and immune cells determined by Mendelian randomization

Year: 2024

Type: article

Abstract: • Establishing Causality: This study employed various two-sample Mendelian randomization (TSMR) techniques, including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, Simple Mode, and Weighted Mode, to effectively confirm the direct causal links between 1400 types of serum metabolites, 731 types of immune cells, and six different types of lymphoma. This finding provides a new genetic perspective on the pathophysiological mechanisms of lymphoma. • Innovative Analytical Techniques: Not only did this study apply standard Mendelian randomization methods, it also included reverse MR analysis and two-step MR mediation techniques. The former was used to explore reverse causality, while the latter quantified the proportion of lymphoma effects mediated by serum metabolites through immune cells. The application of these methods enhanced the rigor of the research design and the interpretative power of the results. • Mediation Analysis: Through two-step MR mediation analysis, this study identified the mediating role of serum metabolites in the development of lymphoma and the function of immune cells. These results reveal potential metabolic pathways that regulate the interaction between immune cell function and lymphoma progression, offering potential intervention points for targeted therapy. • Reliability and Sensitivity: Through MR-Egger regression and leave-one-out sensitivity tests, this study verified the stability and reliability of the results. These tests showed that the analysis was not affected by outliers among the instrumental variables and that there was no significant genetic heterogeneity, thus enhancing the credibility of the study’s conclusions. • Clinical Significance and Future Research: The study’s findings highlight the importance of using immune cells as biomarkers in lymphoma patients. Future research should further explore other potential biomarkers and therapeutic targets, as well as how to optimize treatment strategies through the interaction of immune cells and metabolic pathways. This will help improve the early diagnosis and treatment of lymphoma, while deepening our understanding of targeted immunotherapy and metabolic strategies in the management of lymphoma. Prior research has demonstrated significant roles of metabolites and immune cells in the progression of lymphoma. Mendelian randomization studies have been conducted to assess the causal relationships among serum metabolites, immune cells, and lymphoma, further exploring the mediating role of serum metabolites. Using summary-level data from genome-wide association studies (GWAS), we applied two-sample Mendelian randomization (TSMR) techniques, including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, Simple Mode, and Weighted Mode. These methods were employed to examine the causal links between genetically determined serum metabolites, immune cells, and six types of lymphoma. Additionally, reverse MR analysis investigated reverse causality, and two-step MR quantified the proportion of lymphoma effects mediated by immune cells through serum metabolites. MR-Egger regression and leave-one-out sensitivity tests evaluated the stability and reliability of our findings. The study pinpointed specific serum metabolites and immune cell types causally related to six lymphoma variants. Serum metabolites were identified as mediators in the relationship between immune cells and lymphoma. The two-step Mendelian randomization confirmed this mediated causal relationship, with sensitivity analyses supporting the results’ reliability and lack of pleiotropy. The study establishes a causal connection between immune cells and lymphoma, partially mediated by serum metabolites, although the majority of the influence remains undefined. Future research should explore additional potential mediators. Clinically, there should be an increased focus on immune cells biomarkers for lymphoma patients. These results offer valuable insights for identifying lymphoma biomarkers and potential therapeutic targets.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2024.113593