Jiarui Mi1, Lingjuan Jiang2, Zhengye Liu3, Xia Wu4, Nan Zhao3, Yuanzhuo Wang5, Xiaoyin Bai6. 1. Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China. 2. Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China. 3. Second School of Clinical Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430000, Hubei, China. 4. Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China. 5. Department of Clinical Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100005, China. 6. Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China. baixiaoyin@pumch.cn.
Abstract
BACKGROUND AND AIMS: Observational and Mendelian randomization (MR) studies have identified several modifiable risk factors of cholelithiasis. However, there is limited evidence about the causal effect of blood metabolites on the cholelithiasis risk. METHODS: To have a comprehensive understanding to causal relations between blood metabolites and cholelithiasis, for the primary discovery, we applied two MR methods to explore the associations between 249 circulating metabolites and cholelithiasis. For secondary validations, we replicated the examinations using another metabolic dataset with 123 metabolites. The summary statistics of cholelithiasis were retrieved from FinnGen Consortium Release 5 and UK Biobank. Inverse-variance weighted, weight median and MR-egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal metabolic traits with adjustment for pleiotropy effects. RESULTS: In the primary analysis, sphingomyelin showed consistent protective causal associations with cholelithiasis; while plasma cholesterol-associated traits showed generally inverse correlation with cholelithiasis risk. Notably, large numbers of traits within the (un)saturated fatty acid category demonstrated significant causal effects. Secondary analyses demonstrated similar results, with traits related to the levels of bisallylic groups in fatty acids showing protective effects. Lastly, MR-BMA analyses discovered that the degree of unsaturation plays a predominant role in reducing the risk of cholelithiasis. CONCLUSION: Our MR study provides a complete atlas of associations between plasma metabolites on cholelithiasis risk. It highlighted that genetically predicted sphingomyelin and degree of unsaturation of fatty acid were causally associated with the reduced risk of cholelithiasis.
BACKGROUND AND AIMS: Observational and Mendelian randomization (MR) studies have identified several modifiable risk factors of cholelithiasis. However, there is limited evidence about the causal effect of blood metabolites on the cholelithiasis risk. METHODS: To have a comprehensive understanding to causal relations between blood metabolites and cholelithiasis, for the primary discovery, we applied two MR methods to explore the associations between 249 circulating metabolites and cholelithiasis. For secondary validations, we replicated the examinations using another metabolic dataset with 123 metabolites. The summary statistics of cholelithiasis were retrieved from FinnGen Consortium Release 5 and UK Biobank. Inverse-variance weighted, weight median and MR-egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal metabolic traits with adjustment for pleiotropy effects. RESULTS: In the primary analysis, sphingomyelin showed consistent protective causal associations with cholelithiasis; while plasma cholesterol-associated traits showed generally inverse correlation with cholelithiasis risk. Notably, large numbers of traits within the (un)saturated fatty acid category demonstrated significant causal effects. Secondary analyses demonstrated similar results, with traits related to the levels of bisallylic groups in fatty acids showing protective effects. Lastly, MR-BMA analyses discovered that the degree of unsaturation plays a predominant role in reducing the risk of cholelithiasis. CONCLUSION: Our MR study provides a complete atlas of associations between plasma metabolites on cholelithiasis risk. It highlighted that genetically predicted sphingomyelin and degree of unsaturation of fatty acid were causally associated with the reduced risk of cholelithiasis.
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