The causal relationship between plasma thrombomodulin levels and Risk of Stroke: A Mendelian Randomization Study

Background Evidence of the genetic interconnectedness between thrombomodulin levels (TM) and stroke is largely unclear. This study aims to explore the relationship between genetic predisposition to TM and stroke with a 2-sample, bidirectional Mendelian randomization (MR) method. Methods Genetic instruments for each TM and stroke-related phenotypes were derived from large-scale genome-wide association studies. The inverse variance weighted method was used in the primary analyses to obtain the causal estimates. Complementary sensitivity analyses were conducted to test the robustness of our results. Results Using univariable MR, we found evidence for each standard deviation (SD) increase in genetically predicted TM levels, the odds ratio (OR) was 1.092 (95% confidence interval (CI): 1.034–1.153; p  = 0.002) for any stroke and 1.105 (95% CI: 1.035–1.180; p  = 0.003) for IS. In multivariable MR, the association remained after accounting for body mass index (BMI), systolic blood pressure (SBP), type 2 diabetes (T2D), low-density lipoprotein (LDL) and smoking. Conclusions This MR estimate reveals robust evidence that higher genetically predicted circulating TM levels were associated with an increased risk of any stroke and IS.