Relation of 91 Circulating Inflammatory Proteins to Nonalcoholic Fatty Liver Disease: A Two-Sample Mendelian Randomisation Study

Abstract

Increasingly, emerging research evidence has demonstrated that nonalcoholic fatty liver disease (NAFLD) is a disease closely associated with systemic inflammation. However, the specific upstream inflammatory factors engaged in the pathogenesis of NAFLD remain unclear. Our study aimed to identify the inflammatory regulators causally associated with NAFLD pathogenesis through Mendelian randomisation. A two-sample Mendelian randomisation method was applied to analyse the causal association between 91 circulating inflammatory proteins and NAFLD. Data on circulating inflammatory proteins were derived from samples of European ancestry (14,824 samples) and NAFLD data were obtained from the FinnGen consortium (2025 cases and 284,826 controls). Instrumental variables were selected from the genetic variance and F-statistics were calculated to avoid bias. We adopted the random-effects inverse variance weighting (IVW) method as our primary analytical approach. Supplementary analyses were also implemented, including weighted median, MR-Egger and weighted mode. Moreover, we conducted pleiotropy and heterogeneity analyses to validate the accuracy of the findings. The application of Mendelian randomisation analysis identified four inflammatory factors that might be causally associated with NAFLD at the genetic level. Elevated levels of eotaxin (or = 1.27, 95% CI: 1.05-1.53, p = 0.014), osteoprotegerin (OPG) (or = 1.29, 1.03-1.60, p = 0.023) and TNFRSF9 (or = 1.32, 95% CI: 1.06-1.64, p = 0.014) may be causally related to an increasing risk of NAFLD. Conversely, heightened leukaemia inhibitory factor (LIF) levels (or = 0.63, 0.44-0.92, p = 0.016) were linked to a lower risk of NAFLD onset. There was no causal relationship between levels of other circulating inflammatory proteins and NAFLD. Our analysis uncovered four upstream inflammatory factors genetically associated with the pathogenesis of NAFLD. These results highlight the potential involvement of inflammation in NAFLD, which provides partial insights for further research in this field in the future.

Keywords: Mendelian randomisation study; NAFLD; causal effect; genetic prediction; inflammatory proteins.