title: Relationship between VEGFA polymorphisms and serum VEGF protein levels and recurrent spontaneous miscarriage.
abstract: OBJECTIVE
  Is recurrent spontaneous miscarriage (RSM) associated with changes in vascular endothelial growth factor (VEGF) serum levels, and with polymorphisms in the VEGFA gene?
  
  
  CONCLUSIONS
  Reduced serum VEGF levels, and VEGFA -460T/C (rs833061), 398G/A (rs833068), -583T/C (rs3025020) variants, were associated with RSM.
  
  
  BACKGROUND
  Reduced 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.
  
  
  METHODS
  A retrospective case-control study, which was conducted between January 2011 and April 15, 2012.
  
  
  METHODS
  Subjects 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.
  
  
  RESULTS
  Higher 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.
  
  
  CONCLUSIONS
  The 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.
  
  
  CONCLUSIONS
  Reduced VEGF secretion, and specific VEGFA variants may contribute to the pathogenesis of RSM. However, the association of VEGFA SNPs with RSM appears to be independent of their association with altered VEGF serum levels. The differential association of VEGFA variants with RSM is in line with previous findings on the contribution of ethnicity/racial background to genetic association studies.
authors.affiliation: Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain.
authors.forename: Wassim Y
authors.initials: WY
authors.lastname: Almawi
authors.forename: Fabiola Lisa
authors.initials: FL
authors.lastname: Saldanha
authors.forename: Naeema A
authors.initials: NA
authors.lastname: Mahmood
authors.forename: Intissar
authors.initials: I
authors.lastname: Al-Zaman
authors.forename: Mai S
authors.initials: MS
authors.lastname: Sater
authors.forename: Fekria E
authors.initials: FE
authors.lastname: Mustafa
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics*; D000328:Adult; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D018919:Neovascularization, Physiologic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: haplotypes; miscarriage; polymorphisms; vascular endothelial growth factor