Circulating adipokine concentrations and the risk of venous thromboembolism: A Mendelian randomization and mediation analysis

Weizhong Xiao; Jian Li; Tianyuyi Feng; Long Jin

doi:10.3389/fgene.2023.1113111

Circulating adipokine concentrations and the risk of venous thromboembolism: A Mendelian randomization and mediation analysis

Front Genet. 2023 Mar 28:14:1113111. doi: 10.3389/fgene.2023.1113111. eCollection 2023.

Authors

Weizhong Xiao¹, Jian Li¹, Tianyuyi Feng², Long Jin¹

Affiliations

¹ Department of Interventional Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
² The Department of Radiology of the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.

Abstract

Background: Previous observational studies have suggested that circulating adipokine concentrations are related to a greater risk of venous thromboembolism (VTE). However, it remained unclear whether these observations reflect causality. Objective: This study aimed to investigate the causal relationship between circulating adipokine concentrations (including adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN) and the risk of VTE and its subtypes (DVT and PE) and to determine whether circulating adipokine concentrations are a mediator of venous thromboembolic events in obese patients. Methods: We used Mendelian randomization (MR) analyses to determine the effects of the body mass index (BMI), adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN levels on VTE, DVT, and PE in a cohort of 11,288 VTE cases, 5,632 DVT cases, 5,130 PE cases, and 254,771 controls. We then assessed the proportion of the effect of obesity on VTE, DVT, and PE explained by circulating leptin levels. Result: Genetically predicted higher BMI was related to increased VTE (OR = 1.45, p < 0.001), DVT (OR = 1.63, p < 0.001), and PE (OR = 1.37, p < 0.001) risk, and higher circulating leptin levels increase odds of VTE (OR = 1.96, q < 0.001), DVT (OR = 2.52, q < 0.001), and PE (OR = 2.26, q = 0.005). In addition, we found that the causal effect between elevated serum adiponectin and the decreased risk of VTE (OR = 0.85, p = 0.013, q = 0.053) and PE (OR = 0.81, p = 0.032, q = 0.083) and between MCP-1 and the reduced risk of VTE (OR = 0.88, p = 0.048, q = 0.143) is no longer significant after FDR adjustment. In MR mediation analysis, the mediation effect of circulating leptin levels in the causal pathway from BMI to PE was estimated to be 1.28 (0.95-1.71, p = 0.10), accounting for 39.14% of the total effect. Conclusion: The circulating leptin level is a risk factor for VTE, DVT, and PE, but it might be a potential mediator of BMI on the risk of PE, and thus, interventions on the circulating leptin level in obesity might reduce the risk of PE. Adiponectin is a potential protective factor for both VTE and PE.

Keywords: Mendelian randomization analysis; adipokine; deep vein thrombosis; mediation analysis; obesity; pulmonary embolism; venous thromboembolism.