• Zhanhua Gao, Jie Han, Di Chen, Quan Zhang, and Weiqin Wang.
• Shandong University of Traditional Chinese Medicine Affiliated Hospital, No. 42 Wenhua West Road, Lixia District, Jinan, Shandong Province 250011, China.
• Postgrad Med J. 2025 Jan 27.

BackgroundThe formation of gallstones is a multifactorial process involving lifestyle habits, lipid metabolism disorders, and genetic factors. This study aims to explore the association between 19 types of dietary fatty acids and gallstone disease using large-scale population data, assess the correlation between dietary fatty acids and serum fatty acids, and investigate the causal relationship between plasma lipids and gallstone disease from a genetic perspective.MethodsWe employed a cross-sectional study design, combined with logistic regression analysis to evaluate the association between dietary fatty acids and gallstone disease. Pearson correlation analysis was used to assess the correlation between dietary fatty acids and serum fatty acids. Additionally, we utilized Mendelian randomization analysis to explore the causal relationship between plasma lipids and cholelithiasis and performed collocation analysis to identify genetic loci associated with cholelithiasis.ResultsOur study demonstrated a significant association between the intake of eicosatetraenoic acid (20:4) and a reduced risk of gallstone disease. The correlation between dietary fatty acids and serum fatty acids was weak, but the intake of eicosatetraenoic acid (20:4) showed a positive correlation with serum levels of arachidonic acid (ARA). Mendelian randomization analysis revealed a protective relationship between plasma lipids containing ARA (20:4) and gallstone disease and identified two SNPs in the FADS1 gene(rs174533 and rs174537)associated with gallstone disease.ConclusionsOur study identifies a significant association between ARA intake and reduced gallstone risk, underscoring its potential in gallstone prevention. The weak correlation between dietary and serum fatty acids suggests complex physiological regulation mechanisms. Mendelian randomization analysis establishes a protective causal link between specific plasma lipids containing ARA and gallstone disease, highlighting the genetic underpinnings of gallstone formation. This research provides a foundation for dietary interventions and underscores the importance of genetic factors in lipid metabolism for future gallstone research and clinical management. Key message What is already known on this topic?  Gallstone formation is a multifactorial process, and PUFAs may have a preventive effect, but the specific relationships between dietary fatty acids, serum fatty acids, plasma lipids, and gallstone disease are not well-established. What this study adds?  This study finds a significant association between eicosatetraenoic acid (20:4) intake and reduced gallstone risk, and establishes a protective causal link between plasma lipids containing arachidonic acid (20:4) and gallstone disease through Mendelian randomization analysis. How this study might affect research, practice, or policy?  The results highlight the potential of dietary interventions targeting eicosatetraenoic acid (20:4) for gallstone prevention and underscore the importance of genetic factors in lipid metabolism for gallstone research and clinical management.© The Author(s) 2025. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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