Relationship between VEGFA polymorphisms and serum VEGF protein levels and recurrent spontaneous miscarriage

Abstract

STUDY QUESTIONIs recurrent spontaneous miscarriage (RSM) associated with changes in vascular endothelial growth factor (VEGF) serum levels, and with polymorphisms in the VEGFA gene?SUMMARY ANSWERReduced serum VEGF levels, and VEGFA -460T/C (rs833061), 398G/A (rs833068), -583T/C (rs3025020) variants, were associated with RSM.WHAT IS KNOWN ALREADYReduced expression of VEGF has been linked with spontaneous miscarriage, likely due to defective fetal and placental angiogenesis. Since VEGF production is in part inherited, VEGFA polymorphisms associated with altered VEGF secretion have been investigated for their association with RSM, often with variable conclusions.STUDY DESIGN, SIZE, DURATIONA retrospective case-control study, which was conducted between January 2011 and April 15, 2012.PARTICIPANTS/MATERIALS, SETTING, METHODSSubjects comprised 296 women with RSM (mean age: 31.6 ± 5.4 year), and 305 age-matched (mean age: 31.6 ± 4.9 year) control Arab women, who had attended outpatient obstetrics and gynecology clinics in two teaching hospitals in Bahrain. VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020) and 936C/T (rs3025039) genotyping was done by real-time PCR, with defined clusters; VEGF serum levels were measured by ELISA.MAIN RESULTS AND THE ROLE OF CHANCEHigher minor allele frequency (MAF) and genotype distribution of -460T/C [corrected P (Pc) = 0.003], 398G/A (Pc = 0.016) and -583T/C (Pc < 0.001) single nucleotide polymorphisms (SNPs) were seen in RSM cases than control women. Increased RSM risk was seen with homozygous -460T/C and 398G/A SNPs and with heterozygous -583T/C, which had a stronger effect when homozygous. Serum VEGF levels were significantly reduced in RSM cases compared with control women (P = 0.016), and correlated with -460T/C, 398G/A and -583T/C genotypes. Haploview analysis revealed heterogeneity in linkage disequilibrium between VEGFA variants, and two blocks were identified: Block 1 comprising -2578C/A, -460T/C and -1154G/A, while Block 2 contained -634G/C, 398G/A, 497G/A, -583T/C and 936C/T. Both negatively and positively RSM-associated 3-locus (Block 1) and 5-locus (Block 2) VEGFA haplotypes were identified, after controlling for a number of covariates.LIMITATIONS, REASONS FOR CAUTIONThe study was retrospective and can only demonstrate association and not a cause-effect relationship. Furthermore, it was limited to Bahraini Arabs,thereby necessitating parallel studies on other ethnic groups. © The Author 2013.