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The correlation between sarcopenia and various digestive disorders has been extensively researched, whereas its association with cholelithiasis remains unreported. We aimed to investigate the association through prospective and Mendelian randomization (MR) analyses and establish a quantitative score reflecting the impact of sarcopenia\u2010related markers on cholelithiasis. The prospective study involved 448\u2009627 participants from the UK Biobank. Cox proportional hazard models were employed to investigate the correlation between sarcopenia\u2010related markers and cholelithiasis. To quantitatively assess cholelithiasis risk, the SARCHO score was derived from a multivariable Cox model. Bidirectional two\u2010sample MR analysis was conducted to validate the causal association. A total of 16\u2009738 individuals developed cholelithiasis during a median follow\u2010up of 12\u2009years. Hazard ratios (HRs) of cholelithiasis decreased stepwise over skeletal muscle index tertiles (highest tertile: reference; middle tertile: 1.23, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001; lowest tertile: 1.33, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). The tertiles of grip strength showed a similar pattern. Individuals with slow walking pace had a higher risk of cholelithiasis compared to those with normal walking pace (HR 1.23; <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). Our SARCHO score better quantifies the risk of cholelithiasis. MR analysis showed a causal relationship between muscle mass and cholelithiasis (OR 0.81; <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). No causal effect of cholelithiasis on lean mass was observed. Prospective and MR analyses have consistently demonstrated an increased risk of cholelithiasis in individuals with decreased muscle mass. Additionally, SARCHO score further quantified the cholelithiasis occurrence risk. These findings provide compelling evidence for muscle strengthening in preventing cholelithiasis.<\/jats:p>","DOI":"10.1002\/tox.24215","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T11:14:11Z","timestamp":1709810051000},"page":"3473-3480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Association between sarcopenia\u2010related markers and cholelithiasis: A prospective and Mendelian randomization study"],"prefix":"10.1002","volume":"39","author":[{"given":"Pengcheng","family":"Ma","sequence":"first","affiliation":[{"name":"School of Public Health Southern Medical University  Guangzhou China"},{"name":"School of Health Management Southern Medical University  Guangzhou China"},{"name":"Nanfang Hospital Southern Medical University  Guangzhou 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