Association of polymorphisms/haplotypes of the genes encoding vascular endothelial growth factor and its KDR receptor with recurrent pregnancy loss.

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.