The Role of Mitochondrial DNA Copy Number in Venous Thromboembolism: Insights from a 2-Sample Mendelian Randomization Study.

Background: Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is the third most common cardiovascular disease. A low amount of mitochondrial DNA copy number (mtDNA-CN) reflects mitochondrial dysfunctions and has been associations with arterial cardiovascular diseases. However, the role of mtDNA-CN in venous cardiovascular disease was unclear. We aimed to implement a 2-sample Mendelian randomization analysis to approximate the causal nature of these relationships.

Methods: Genetic instruments for VTE, PE, and DVT were derived from the largest available genome-wide association study datasets. The inverse variance weighted method was used as the primary analytical approach, with sensitivity analyses performed to assess horizontal pleiotropy and heterogeneity. The reverse Mendelian randomization analysis was conducted using genetic instruments for mtDNA-CN.

Results: The genetically instrumented mtDNA-CN levels did not exhibit a causal effect on VTE (P = 0.224), DVT (P = 0.190), and PE (P = 0.571). However, genetically predicted VTE (odds ratio (OR) = 0.569, 95% confidence interval (CI) = 0.341-0.952; P = 0.032), PE (OR = 0.991, 95% CI = 0.983-0.999; P = 0.037), and DVT (OR = 0.429, 95% CI = 0.207-0.890; P = 0.023) were associated with decreased mtDNA-CN levels in the inverse variance weighted analysis. Sensitivity and replication analyses confirmed the robustness of these findings.

Conclusion: Our findings did not support a causal effect of mtDNA-CN in the development of VTE, but provide direct evidence that VTE may lead to reduced mtDNA-CN levels. These results suggest that mtDNA-CN as a biomarker of VTE in clinical practice.