Immune cells and blood lipids mediation: a Mendelian randomization study on metabolic dysfunction-associated fatty liver disease

Background: The current understanding of the relationship between immune cells and metabolic dysfunction-associated fatty liver disease (MAFLD) is limited. The purpose of this study was to examine the causal role played by immune cells in MAFLD. Methods: To investigate the causal association between immune cells and MAFLD, two-sample Mendelian randomization (MR) studies were conducted. Summary statistics were obtained from genome-wide association studies (GWASs) of 731 immune traits (4 types and 7 panels) and from the two largest meta-GWASs of MAFLD. Thorough reverse and sensitivity analyses were utilized to validate the strength of the findings. Mediation MR analyses were performed to investigate the potential mediating effects of various MAFLD risk factors, such as blood lipids, on the relationship between immune traits and MAFLD. Results: We found that genetically predicted higher CD25 expression on IgD- CD38dim B cells (OR = 0.93, 95% CI = 0.88–0.99) was associated with a lower risk of developing MAFLD. The proportion of genetically predicted CD25 on IgD- CD38dim B cells mediated by high-density lipoprotein cholesterol (HDL-C) was 2.21% and that on Apolipoprotein A1 is 1.91%. During the reverse analysis of the significant impact of NAFLD on immunophenotype, the leukocyte AC TBNK (OR = 1.66, 95% CI = 1.22 ~ 2.27) was identified. Conclusion: Our study provides genetic evidence regarding the role of CD25 on IgD- CD38dim B cells in MAFLD mediated by blood lipids and supports a causal association between various immune cells and MAFLD.