Causal association between plasma vascular endothelial growth factor family proteins and placenta previa

Abstract

This study investigates associations between genetically proxied plasma vascular endothelial growth factor (VEGF) family proteins and placenta previa using 2-sample Mendelian randomization (MR). Exposure GWAS summary statistics were obtained from the UK Biobank and IEU resources, and placenta previa data from FinnGen. Inverse-variance weighted (IVW) analysis was the primary method, supplemented by MR-Egger, weighted median, and weighted mode analyses. The Bonferroni-corrected threshold for 5 exposures was P < .01. Cochran Q, the MR-Egger intercept, MR-PRESSO and leave-one-out analyses assessed heterogeneity and sensitivity. Genetically predicted higher plasma VEGFA was associated with increased placenta previa risk (IVW: β = 0.231, OR = 1.26, 95% confidence interval: 1.06–1.51, P = .008). The analyses did not provide statistically convincing evidence of a causal effect of VEGFB, VEGFC, VEGFD, or placental growth factor (PLGF); these findings should not be interpreted as evidence of no effect. For VEGFA specifically, Cochran Q test did not detect significant heterogeneity (IVW: Q = 21.257, P = .729), and the MR-Egger intercept (−0.026, P = .181) and MR-PRESSO global test (P = .692) did not detect evidence of horizontal pleiotropy. The VEGFA leave-one-out analysis indicated that no single SNP substantially influenced the estimate. In contrast, VEGFD showed a significant MR-Egger intercept (−0.155, P = .029), indicating possible directional horizontal pleiotropy and requiring particular caution in interpreting this exposure. The findings support an association between genetically proxied plasma VEGFA and placenta previa risk. They provide etiologic insight rather than evidence of clinical prediction; any predictive or screening role for VEGFA measurement requires prospective, pregnancy-specific validation.