BACKGROUND Vascular endothelial growth factor (VEGF) and its kinase insert domain receptor (KDR) play an important role in angiogenesis, and their gene expression patterns also suggest a close relationship with early pregnancy. However, limited information is available regarding the role of the VEGF system, especially its KDR receptor, in recurrent pregnancy loss (RPL). This study was conducted to investigate a genetic association between VEGF and its receptor gene (KDR) with idiopathic RPL. METHODS In this case-control study, 115 women who had experienced at least two consecutive spontaneous miscarriages (n= 62 women with two miscarriages, n= 53 with three or more) and 170 controls were included. A total of 14 tag single-nucleotide polymorphisms (SNPs) of VEGF and KDR were selected from the HapMap Web site and three functional SNPs [rs1570360 (-1154G/A) of VEGF; rs2305948 (V297I) and rs1870377 (Q472H) of the KDR gene] were genotyped using primer extension analysis. We further used multifactor dimensionality reduction analysis to evaluate gene-gene interactions. RESULTS One tag SNP (rs6838752) and the functional SNP (Q472H) of the KDR gene were in complete linkage and showed significant differences between patients and controls (P< 0.05). The frequencies of haplotypes of VEGF (A-T-G haplotype) and KDR (A-C-A-T-G haplotype) showed significant differences in patients versus controls (P< 0.05). All comparisons with controls remained significant when the subgroup of women with three or more miscarriages was analyzed. CONCLUSIONS VEGF and its receptor gene (KDR) are associated with idiopathic RPL. The VEGF/KDR system jointly contributes to recurrent miscarriage in Taiwanese Han women.

Purpose Recurrent pregnancy loss (RPL) could be caused by insufficient progesterone in the luteal phase of menstruation and early pregnancy. Progesterone plays a critical role in oocyte maturation, embryo implantation and placenta maintenance in early gestation. This study was set out to investigate the association between polymorphisms of the progesterone receptor (PGR) gene and idiopathic RPL. Methods One hundred twenty-one women with a history of idiopathic recurrent pregnancy loss (RPL) and 179 control subjects were enrolled into the study. Six tag SNPs and two functional SNPs [PROGINS (rs1042838), +331 C/T (rs10895068)] of the progesterone receptor gene were genotyped. Results We found that the allele and genotype frequencies of the functional SNP [PROGINS (rs1042838)] were both significantly higher in patients with idiopathic RPL than in the control subjects (both P values=0.006). In addition, the C-C haplotype, which consists of rs590688C>G and rs11224592T>C, is associated with a decreased risk of RPL (p=0.004). Conclusion PROGINS polymorphism confers susceptibility to idiopathic recurrent pregnancy loss in Taiwanese Han women.

EG-VEGF receptor (PKR1, PKR2) gene polymorphisms and haplotypes were associated with idiopathic RPL. These three genes (EG-VEGF, PKR1 and PRK2) jointly contribute to RPL in the Taiwanese Han population.

This study was supported by grants from the National Science Council of the Republic of China (NSC-100-2314-B-006-011-MY3). None of the authors have any conflicts of interest.