Therapeutic targets for gastrointestinal diseases: proteome-wide Mendelian randomization and colocalization analyses

Purpose This study was aimed to identify serum proteins linked with gastrointestinal diseases by proteome-wide Mendelian randomization analysis.Methods We determined the casual relationship between 732 kinds of circulating proteins and the 24 kinds of gastrointestinal diseases via Mendelian randomization analysis.Results Four circulating proteins (FCGR3B, IL-12B, MAPKAPK2, and IL-23R) were associated with the occurrence of ulcerative colitis (UC), and IL23R was also correlated with risk of Crohn's disease (CD). Genetically predicted levels of IL23R were strongly correlated with the risk of UC and CD based on the high supporting evidence of colocalization analysis. Five circulating proteins (NOV, EFEMP1, ADGRE2, LCT, and SEMA3G) were associated with the risk of diverticulosis disease. With high supporting evidence of colocalization, genetically predicted levels of NOV and SEMA3G were inversely correlated with the risk of diverticulosis disease. Five circulating proteins (FUT3, FUT5, CRHBP, SULT2A1, and QPCTL) were associated with the occurrence of cholelithiasis. With high supporting evidence of colocalization, genetically predicted levels of FUT3 and CRHBP were inversely correlated with the risk of cholelithiasis.Conclusions The proteome-wide Mendelian randomization investigation identified several circulating proteins associated with the risk of UC, CD, diverticular disease and cholelithiasis, which reinforced the understanding of molecular pathogenesis and design of therapeutic targets. Key messages What is already known on this topic The proteome-wide Mendelian randomization analysis is a well-established method to identify novel therapeutic targets, but no study has comprehensively used this method to identify potential therapeutic targets for 24 kinds of gastrointestinal diseases. What this study adds This study identified four protein-UC associations, one protein-CD association, five protein-diverticular disease associations and five protein-cholelithiasis associations. How this study might affect research, practice or policy Our study reinforced the understanding of molecular etiology and design of therapeutic targets of 4 kinds of gastrointestinal diseases. We need to validate the role of these proteins in the above gastrointestinal diseases both from the basic researches and clinical trials, for the purpose of designing novel agents in the future.