Genetic insights into visceral obesity with health conditions, from disease susceptibility to therapeutic intervention

Purpose: This 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 design: Univariable 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.

Results: Visceral 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.

Conclusions: This 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.