Association of Variants in Vascular Endothelial Growth Factor A Gene and VEGFA Serum Levels with the Risk of Primary Ovarian Insufficiency: A Case-Control Study

Objective: The study aimed at investigating the association between the vascular endothelial growth factor A (VEGFA) genetic variants, the VEGFA serum level, and the primary ovarian insufficiency (POI) risk in Chinese Han women. Design: An age-matched case-control study was implemented in the West China Second Hospital of Sichuan University. Participants/Materials, Setting, Methods: Blood samples and clinical information were collected from 240 patients with POI and 261 healthy controls between December 2012 and December 2018 at the West China Second Hospital of Sichuan University. Mutations of VEGFA gene -2578C/A, -1154G/A, 936C/T, and -634C/G were identified by PCR-RFLP. Moreover, VEGFA serum levels in the 2 groups were measured by the enzyme-linked immunosorbent assay (ELISA). Results: The -1154G>A and 936C>T variants of the VEGFA gene were significantly associated with POI (the adjusted odds ratio [OR] = 2.17 and 95% confidence interval [CI] = 1.07-4.43 for the former; the adjusted OR = 2.74 and 95% CI = 1.18-6.34 for the latter), whereas no significant difference was found in the genotype distribution of -2578C>A and -634C>G variants between patients and controls (p > 0.05). Moreover, the combined -1154G>A and 936C>T genotype was associated with a significantly increased risk of POI (the adjusted OR = 21.98, 95% CI = 2.78-173.78 among subjects carrying 3 or more variants), particularly when patients aged >= 35 years (the adjusted OR = 20.58, and 95% CI = 2.58-164.25). The POI group exhibited an obviously lower VEGFA serum level (45.15 +/- 1.25 pg/mL) than the control group. Compared with the control, the expression of VEGFA was significantly decreased in the POI group (279.90 +/- 5.71 pg/mL; p < 0.05). Moreover, the serum VEGFA levels are lower in the -1154AA genotype than those of AG/GG genotypes. Limitations: The main limitation is that all participants enrolled in this study were Chinese. As genotype and allelotype frequencies tend to differ between ethnic populations, extrapolation of the results to other ethnic groups should be cautiously considered. Conclusions: Our study indicates an association between the VEGFA -1154G/A, 936C/T variants, and susceptibility to POI in Chinese Han women. Reduced levels of VEGFA may be a potential mechanism for the de-velopment of POI.