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

Abstract 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.