Analysis of VEGFA Variants and Changes in VEGF Levels Underscores the Contribution of VEGF to Polycystic Ovary Syndrome

Background Vascular endothelial growth factor (VEGF) contributes to the pathogenesis of polycystic ovary syndrome (PCOS), and genetic variations in VEGFA gene were suggested to contribute to VEGF secretion and PCOS. Aim To evaluate the association of altered VEGF levels, stemming from the presence of specific VEGFA variants, with altered risk of PCOS. Subjects and Methods Retrospective case-control study, performed between 2012-2015. Study subjects comprised 382 women with PCOS, and 393 control subjects. ELISA measured VEGF levels; genotyping of VEGFA variants was done by allelic exclusion. Results Among the 12 tested VEGFA SNPs, minor allele frequency of only rs3025020 was significantly higher in PCOS cases than control women. Increased and reduced PCOS risk was seen with rs3025020 and rs2010963 genotypes, respectively. Increases and reduction in VEGF levels were associated with rs3025020 and rs2010963, respectively. Increased fasting insulin and HOMA-IR, and bioactive testosterone were linked with rs3025020, while carriage of rs2010963 was linked with reduction in fasting insulin, and free and bioactive testosterone. Of the 12 VEGFA variants, 9 were in LD, thus allowing construction of 9-locus haplotypes. Increased frequency of CAACAGCGA haplotype was seen in PCOS cases, after controlling for BMI, free and bioactive testosterone, SHBG, free insulin and HOMA-IR. Conclusion This study confirms the contribution of altered VEGF secretion, resulting from genetic variation in VEGFA gene into the pathogenesis of PCOS. This supports a role for VEGF as PCOS candidate locus.