IL-1β Signaling, Obesity, and Venous Thromboembolism: A Mendelian Randomization Study

Anticoagulation is standard treatment for venous thromboembolism (VTE) but increases the risk of bleeding. Anti-inflammatory treatment has been shown to be effective in thrombosis. However, research on the potential of anti-inflammatory targets and the interleukin-1 beta (IL-1β) pathway for VTE is lacking. Obesity is accompanied by low-grade chronic inflammation, which increases the risk of VTE. We aimed to investigate the causal relationship between IL-1β signaling, obesity, and VTE.

We performed a two-sample and two-step Mendelian randomization to investigate the relationship between IL-1β signaling, obesity-related traits (body mass index [BMI], waist circumference, and waist-to-hip ratio), and VTE (deep vein thrombosis, pulmonary embolism [PE]) and the mediating effect of obesity. Genetic instruments for IL-1β signaling were identified as genetic variants, which were both associated with the expression of the IL-1β gene and neutrophil count.

Decreased IL-1β signaling was associated with reduced risk of PE (odds ratio = 0.06 [95% confidence interval (CI) 0.01, 0.33], P = 0.001). Among 3 obesity-related traits, BMI was associated with IL-1β signaling and PE. A significant effect of the IL-1β pathway on PE, mediated by BMI, was documented (0.92 [0.91, 0.94], P = 0.018), with an estimated proportion of 2.78% (95% CI [0.46%, 5.10%]) of the total effect.

The study supported an association between decreased IL-1β signaling and reduced risk of PE. BMI appeared to mediate this effect. The result provides supporting data for potential anti-inflammatory treatment in VTE. The associations between IL-1β signaling, BMI, and PE need further investigation.