Circulating cytokines and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study

AbstractBackground Increased inflammation in the liver during ethanol exposure is a major feature of alcoholic liver disease (ALD). An important contributing component to the development of ALD is the inflammatory response brought on by immunological response, however the connection between individual circulating cytokines and ALD is still unclear. To ascertain the causation, we conducted a two-sample bidirectional Mendelian randomization research.Methods We extracted 41 cytokines and growth factors of 8293 Europeans and ALD cases of the same ethnicity (1416 cases and 217,376 controls) from the Genome-Wide Association Studies (GWAS) database for two-sample bidirectional MR analysis.Results Our analyses suggest that higher interleukin-7 (IL-7) levels are associated with an increased risk of ALD (p = 0.028, OR = 1.191,95% CI = 1.019–1.392), while tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a protective factor for ALD (p = 0.032, OR = 0.863, 95% CI = 0.754–0.988) which can reduce the risk of disease occurrence. In addition, genetically predicted ALD does not affect the expression of circulating cytokines regulators.Conclusions Our study supports that cytokines play a pivotal role in the pathogenesis of ALD. To determine the mechanisms and pathways of action of these biomarkers, further basic research is required to ensure their clinical suitability for preventing and treating ALD.Keywords: Alcoholic liver diseasecirculating cytokinesmendelian randomizationinterleukin-7TRAIL AcknowledgmentsWe thank all the researchers in this MR study. The Data on ALD, and circulating cytokines were searched from GWAS data, we thank all investigators.Authors contributionsDW, OYH and WYH contributed to conception and design of the study. DW, OYH, WYH, LKB and ZRW performed the statistical analysis. DW wrote the first draft of the manuscript. JFZ and HYW made conceptualization and guidance of the overall article. All authors contributed to manuscript revision, read, and approved the submitted version.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementThe data presented in this study are openly available in MRC IEU Open GWAS database (https://gwas.mrcieu.ac.uk/). Data on circulating cytokines at PMID: 27989323 and ALD from FinnGen at opengwas id:finn-b-ALCOLIVERAdditional informationFundingThis work was supported by grants from preclinical study of a new Chinese herbal medicine for the treatment of ascites of liver cirrhosis (spleen and kidney yang deficiency type) with the clinical formula of Qigui Xiaogu Cataplasm. (No. 23S21900100), National Natural Science Foundation of China (82074386), Construction of special disease alliance of traditional Chinese medicine in East China area and municipal level, Shanghai special disease alliance of traditional Chinese medicine for liver cirrhosis ascites (Water sickness), Traditional Chinese Medicine/Chinese and Western Medicine advantage specialty construction specialty of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (YW(2023-2024)-01-03) and Clinical Research Plan of SHDC (No. SHDC2020CR3095B) for Junfeng Zhu.