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

BACKGROUND: Vascular endothelial growth factor (VEGF) has angiogenic and possibly proatherosclerotic properties. Observationally it is positively associated with cardiovascular disease, although these observations could be confounded or due to reverse causation. We assessed ischemic heart disease (IHD) risk by genetically predicted VEGF, ie, using Mendelian randomization. METHODS AND RESULTS: Single nucleotide polymorphisms (SNPs) predicting VEGF level, at genome‐wide significance, were applied to the CARDIoGRAMplusC4D 1000 Genomes‐based genome‐wide association study IHD case (n=60 801)‐control (n=123 504) study. We obtained unconfounded estimates using instrumental variable analysis by combining the Wald estimates for each SNP using inverse variance weighting and Mendelian randomization–Egger regression. Based on 9 SNPs independently predicting VEGF (rs1740073 [C6orf223], rs2375981 [KCNV2], rs2639990 [ZADH2], rs4782371 [ZFPM1], rs6921438 [LOC100132354], rs7043199 [VLDLR‐AS1], rs10761741 [JMJD1C], rs6993770 [ZFPM2], and rs114694170 [MEF2C]), VEGF was unrelated to IHD (odds ratio 0.99 per log‐transformed pg/mL, 95%CI 0.96‐1.02) using inverse variance weighting. However, Mendelian randomization–Egger regression suggested an inverse relation of VEGF with IHD (odds ratio 0.95, 95%CI 0.91‐0.99), although the association was not evident after excluding the lead SNP (rs6921438) or additionally excluding the pleiotropic SNP (rs6993770). CONCLUSIONS: Our study does not provide strong evidence for a positive effect of VEGF on IHD but does not rule out the possibility that some specific types of VEGF, for which genetic predictors have not yet been identified, might play a role.