Effects of Vascular Endothelial Growth Factor Family on Macular Pucker:cis-Mendelian Randomization and Colocalization Analyses

Background Vascular endothelial growth factor (VEGF) family and its receptors (VEGFR) could be implicated in macular pucker (MP) pathogenesis. We used cis -Mendelian randomization ( cis -MR) and Bayesian colocalization with summary-level genome-wide association study (GWAS) data to explore causal relationships. Methods Genetic variants associated with soluble VEGFR2 (sVEGFR2), sVEGFR3, VEGF-A, VEGF-C, or VEGF-D levels were selected from a GWAS of protein quantitative trait loci with 35,559 Icelanders. MP GWAS (3,974 cases, 376,650 controls) was sourced from the FinnGen. We employed cis -MR using invariance-weighted median, supplemented by other methods. Bayesian colocalization validated cis -MR findings. Pleiotropy, reverse causality, and heterogeneity were assessed. Findings Cis -MR suggested that genetically predicted higher levels of sVEGFR2 were associated with reduced MP risk (Odds ratio (OR) 0.82, 95% confidence interval (CI) 0.75-0.89, P=9.20 × 10 -6 ). Colocalization supported shared genetic variants in the VEGFR2 gene region between sVEGFR2 and MP (posterior probability of hypothesis 4 (PPH 4 ) =0.94), reinforcing sVEGFR2’s protective role in MP. Although cis -MR suggested an inverse relationship between sVEGFR3 levels and MP risk (OR 0.71, 95% CI 0.57-0.89, P=2.64 × 10 -3 ), colocalization analysis did not confirm direct causality (PPH 4 =0.03). VEGF-A, VEGF-C and VEGF-D levels were not associated with MP risk in MR analyses. No evidence of pleiotropy, reverse causality, and heterogeneity was found across our MR analyses. Interpretation Our study suggested that sVEGFR2 has causally protective effects against MP and could serve as a potential drug target. Further research is necessary to elucidate its protective mechanisms and validate its translational implications.