Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study

Area of Science:

• Genetics
• Cardiovascular Science
• Epidemiology

Background:

• Conflicting evidence exists regarding the association between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS).
• Mendelian randomization (MR) offers a robust approach to investigate potential causal relationships by utilizing genetic variants as instrumental variables.

Purpose of the Study:

• To determine the causal effect of serum vascular endothelial growth factors (VEGF) on the risk of ischemic stroke (IS) and its subtypes.
• To leverage Mendelian randomization to overcome confounding factors present in observational studies.

Main Methods:

• Utilized summary statistics from large-scale genome-wide association studies (GWAS) for VEGF levels (n=16,112) and IS (n=40,585).
• Employed the inverse variance-weighted (IVW) method for primary analysis, with MR-Egger regression and weighted median as sensitivity analyses.
• Investigated primary outcome (any IS) and secondary outcomes (large-artery, cardioembolic, and small-vessel stroke).

Main Results:

• Nine single nucleotide polymorphisms (SNPs) were identified as genetic proxies for serum VEGF levels.
• The primary IVW analysis showed no significant causal association between genetically predicted VEGF levels and any IS (OR 1.01, p=0.39).
• Sensitivity analyses and MR-Egger regression confirmed the robustness of these findings, indicating no significant causal link and no evidence of horizontal pleiotropy.

Conclusions:

• This Mendelian randomization study provides strong evidence that genetically determined serum VEGF levels are not causally associated with the risk of ischemic stroke.
• The findings suggest that VEGF may not be a viable therapeutic target for preventing ischemic stroke based on genetic predisposition.