Interleukins and the risk of non-alcoholic fatty liver disease: a two-sample Mendelian randomization study

Abstract

Abstract Background and Aims: Interleukins (ILs) are associated with non-alcoholic fatty liver disease (NAFLD), however the direction and causal effects of them susceptibility remain unclear. Two-sample Mendelian randomization (MR) study was performed to investigate the causal relationship. Materials and Methods: Single nucleotide polymorphisms associated with 10 ILs were used as instrumental variables. Summary-level results of estimates for the associations of NAFLD were obtained from two large multi-centered NAFLD genome-wide association study (2,377 cases and 23,5679 controls). For univariable MR, inverse-variance weighted (IVW) method was applied, while MR-Egger, Weighted Median and MRPRESSO were conducted as sensitivity analyses. Lastly, we performed meta-analyses with estimates from the two cohorts. Results: IL-1 receptor antagonist (IL-1Ra) demonstrated a suggested significant association with an increased risk of NAFLD in both cohorts, with OR 1.435 (95%CI, 1.041-1.977, P=0.0270) and 1.424 (95%CI, 1.011-2.004, P=0.0430), respectively. The combined estimate OR 1.430 (95%CI, 1.132-1.807, P=0.0027). Furthermore, genetically proxied IL-6 and IL-6 receptor alpha (IL-6Ra) levels displayed consistent positive trend with an increased risk of NAFLD, although none of them reach suggestive significance. Notably, the pooled estimates were 1.827 (95% CI, 1.328-2.514, P=0.0002) for IL-6 and 1.098 (95% CI, 1.026-1.176, P=0.0068) for IL-6Ra, respectively. The sensitivity analysis showed consistent positive trend towards the increased NAFLD susceptibility, though none of them achieved statistical significance. Conclusion: The results suggested genetically proxied circulating of IL-1Ra, IL-6, and IL-6Ra are causally associated with the risk of NAFLD. Moreover, our data highlights the potential targeted measures and drug repurposing strategies in the NAFLD prevention and treatment.