Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study.

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is a globally widespread disease. Recent investigations have highlighted a close association between immunity and NAFLD, but the causality between them has not been thoroughly examined.

Methods: A total of 731 immunological traits and NAFLD cohorts were derived from genome-wide association study summary data, and single nucleotide polymorphisms significantly associated with immune traits were identified as instrumental variables. Moreover, 731 phenotypes include absolute cell counts, median fluorescence intensity (MFI), morphological parameters, and relative cell counts. The bidirectional two-sample Mendelian randomization (MR) was performed primarily using the inverse-variance weighted methods, and sensitivity analysis was carried out simultaneously.

Results: Four immunophenotypes were identified to exert a protective effect against NAFLD, including HLA-DR⁺ CD4⁺ %lymphocytes, SSC-A on CD4⁺, CD24 MFI on IgD^-CD38^-, and CD8 MFI on CD28^-CD8^br. Seven immunophenotypes were identified to be hazardous, including CD28⁺ CD45RA⁺ CD8^dim%CD8^dim, CD127 MFI on CD28⁺ DN (CD4^-CD8^-), CD20 MFI on IgD⁺ CD38^br, CD20 MFI on transitional, IgD MFI on transitional, CD3 MFI on central memory CD8^br, and CD45 MFI on CD33^brHLA-DR⁺ CD14^-. However, reverse MR showed NAFLD had no causal effect on immunophenotypes.

Conclusion: The study demonstrated a potential causal link between several immunophenotypes and NAFLD, which contributes to advancing research and treatment of NAFLD based on immune-mediated mechanisms.