• Genshan Zhang, Baolin Han, Yanghui Chen, Wei Jiang, Jie Fu, Xiangshang Xu, Xuelai Luo, and Zhixin Cao.
• Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Av, Wuhan 4300030, PR China.
• Postgrad Med J. 2025 Jan 21.

PurposeThis study aimed to investigate the relationship between visceral obesity and various disease traits, as well as to identify potential safe targets for the prevention and treatment of visceral obesity.Study DesignUnivariable and multivariable Mendelian randomization (MR) analyses were performed to examine the associations between visceral obesity and 1883 disease traits. Furthermore, we assessed the potential effect of 1684 protein expressions on visceral obesity using the available quantitative trait locus data for plasma proteins. To evaluate the potential safety profiles associated with biomarker intervention, we conducted phenome-wide MR using 1883 outcomes, focusing on the significant biomarkers.ResultsVisceral obesity was significantly associated with elevated risks of 183 disease traits across multiple systems, such as endocrine, cardiovascular, respiratory, digestive, musculoskeletal, and genitourinary systems. Higher genetically predicted levels of GCKR, CYB5A, ITPKA, and ENTPD6 were found to increase the risk of visceral obesity, while 1433B, SEMA3G, FOXO3, and HAPLN4 were associated with a decreased risk of visceral obesity. The results of the phenome-wide MR analysis indicate that CYB5A, ENTPD6, 1433B, and HAPLN4 can potentially be safe and effective drug targets for visceral obesity treatment.ConclusionsThis study indicates visceral obesity is associated with an increased risk of diseases within various physiological systems, such as cardiovascular, respiratory, and endocrine systems. The circulatory proteome reveals eight novel biomarkers for visceral obesity intervention, with CYB5A, ENTPD6, 1433B, and HAPLN4 displaying particular potential as safe and effective drug targets.© 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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