Causal Association Between Circulating Inflammatory Proteins and Autoimmune Liver Disease: a Bidirectional Two-Sample Mendelian Randomization Study

Lina Leng,1,* Ying Li,2,* Tao Xu,3 Jingfang Shen,1 Lianju Li,1 Xiaoli Li1 1Department of Rheumatology, Xingtai People’s Hospital, Xingtai, 054001, Hebei Province, People’s Republic of China; 2Department of Oncology, 82 Group Hospital of Chinese People’s Liberation Army, Baoding, Hebei Province, 071000, People’s Republic of China; 3Department of Internal Medicine, Graduate School of Hebei North University, Zhangjiakou, Hebei Province, 075000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoli Li, Email [email protected]: To investigate whether there is a direct causal relationship between circulating inflammatory proteins and autoimmune liver disease (AILD).Materials and Methods: We collected genetic data for various AILD from the Genome Wide Association Studies (GWAS) dataset. The latest research provides GWAS data for 91 proteins associated with inflammation. Perform bidirectional two sample Mendelian randomization (MR) analysis using inverse variance weighted (IVW) to determine the causal relationship between inflammatory proteins and AILD, and use Mendelian randomization Egger method (MR Egger), weighted median (WM), and weighted mode as supplementary evaluations. In addition, we conducted sensitivity analysis.Results: Positive MR analysis showed that CDCP1 (OR=1.363, p=0.0465) and IL-18 (OR=1.416, p=0.0477) were associated with higher including autoimmune hepatitis (AIH) risk. Higher CXCL11 (OR=1.574, p=9.23× 10-5) were associated with an increased risk of primary biliary cholangitis (PBC). Lower levels of three inflammatory proteins were associated with increased risk of PBC. TNFSF12 (OR=1.827, p=0.0001, p_adj_fdr=0.0063), CD6 isoform (OR=1.126, p=0.0389), CCL20 (OR=1.880, p=0.0395) are associated with increased risk of primary sclerosing cholangitis (PSC). Reverse MR imaging showed that PBC may promote the expression levels of CCL4 (OR=1.023, p=0.0201) and OSM (OR=1.022, p=0.0236). PSC may promote the expression of five inflammatory proteins. Sensitivity analysis further excluded the effects of heterogeneity and horizontal pleiotropy.Conclusion: This study indicates a potential association between circulating inflammatory proteins and AILD, which may become a new diagnostic indicator or drug target for clinical application in the prevention and treatment of AILD. However, further investigation is needed.Keywords: autoimmune liver disease, Mendelian randomization, circulating inflammatory protein, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis