Causality between cholelithiasis and ileus: a two-sample Mendelian randomization study

Abstract Background: Cholelithiasis is a prevalent digestive ailment in China, prompting extensive research on its association with ileus. However, prior investigations relied on observational methodologies, introducing biases. To enhance objectivity, we adopted the Mendelian randomization method for a more comprehensive understanding. Methods: We selected single nucleotide polymorphisms (SNPs) strongly correlated with cholelithiasis as instrumental variables from large-scale population-wide genome-wide association studies (GWAS). Ileus outcomes were sourced from the IEU Open GWAS database (Ileus: GWAS ID: ebi-a-GCST90018867; 2911 cases, 395,721 controls). Using analytical approaches like inverse variance weighting (IVW) and MR-Egger regression, we assessed causality. A sensitivity analysis, considering factors like horizontal pleiotropy, was conducted (Figure 1). Results: (1) Inverse variance weighting revealed a significant association between K80 cholelithiasis (GWAS ID: ukb-a-559) and ileus (GWAS ID: ebi-a-GCST90018867). Additionally, a correlation emerged between cholelithiasis (GWAS ID: ukb-a-71) and ileus (GWAS ID: ebi-a-GCST90018867). A distinct cholelithiasis subtype (GWAS ID: ukb-b-18700) demonstrated a causal relationship with ileus (GWAS ID: ebi-a-GCST90018867). (2) The MR-Egger method, assessing horizontal pleiotropy, found no evidence of its existence (GWAS ID: ukb-b-18700, P= 0.034). (3) This Mendelian randomization study provides compelling evidence supporting a causal link between cholelithiasis and ileus. Such findings enhance our understanding of ileus etiology and pathogenesis, with crucial clinical implications for prevention, early diagnosis, and treatment. Conclusion: A causal link between cholelithiasis and ileus is confirmed through thorough Mendelian randomization analysis. This discovery has substantial potential to provide key insights for preventing, detecting early, and implementing effective treatment strategies for ileus.