A Bidirectional two-Sample Mendelian Randomization Study of the Association Between Venous Thromboembolism and Ischaemic Stroke

Abstract

Previous clinical and epidemiological studies have shown that patients with venous thromboembolism (VTE) are comorbid with symptoms of ischaemic stroke (IS). Current understanding about increased risk of IS after VTE remain inconclusive. This study use a bidirectional two-sample Mendelian randomization (MR) study to explore the causality of VTE, pulmonary embolism (PE), deep vein thrombosis (DVT), and IS. This study used pooled data from published genome-wide association studies (GWAS). GWAS statisics of IS (from EBI database, n = 484 121), VTE (from Finngen database, n = 218 792), PE (from Finngen database, n = 218 413), and DVT (from UK biobank database, n = 337 159) were assessed. Forward and reverse MR analysis were conducted to explore the causal relationship between three type of the exposure (VTE, PE, and DVT) and the outcome (IS). Our primary causal inference method was Inverse Variance Weighted (IVW). Secondary inference methods were Weighted Median and MR-Egger. For the sensitive analysis, MR-PRESSO, MR-Egger intercept, Cochran's Q, leave-one method were used to consolidate our findings. In the foward MR analysis, VTE increased the risk of IS (OR_IVW = 1.034, P_IVW = 0.021) and PE was also a risk factor for IS (OR = 1.055, P_IVW = 0.009). There was no causality that DVT influenced on IS (P_IVW > 0.05). In the reverse MR analysis, IS came to be a risk factor for DVT (OR = 1.003, P_IVW = 0.046). Meanwhile, IS took not any causal effect on VTE and PE. All the results passed the reasonable sensitive analysis. Our findings provided genetic evidence that PE and VTE can lead to an increased risk of IS, whereas increased IS promoted the risk of DVT further. Our findings provided novel insights about the risk factors and management for IS.

Keywords: deep vein thrombosis; ischemic stroke; mendelian randomization; pulmonary embolism; venous thromboembolism.

Figure 1.

The fowchart of the MR research.

Figure 2.

The scatter plots about the forward and reverse MR analysis. (A) VTE on IS; (B) PE on IS; (C)DVT on IS; (D) IS on VTE; (E) IS on PE; (F) IS on DVT. Venous thromboembolism:VTE; Pulmonary embolism:PE; Deep vein thrombosis:DVT; Ischaemic stroke:IS.