The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss

Abstract

Purpose The role of genetic polymorphisms in the pathogenesis of recurrent pregnancy loss (RPL) has been studied intensively.Complex diseases, including miscarriage, are believed to have a polygenic basis, and gene–gene interactions can play a significant role in the etiology of the disease. This study was conducted to investigate the association of gene–gene interactions with angiogenesis, endothelial dysfunction-related gene polymorphisms, and RPL. Methods Acase–control study was conducted with 253 unrelated RPL patients with 2 or more spontaneous pregnancy losses and 339 healthy women with no history of pregnancy complications. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using real-time polymerase chain reaction (real-time PCR), restriction fragment length polymorphism (RFLP), or allele-specific polymerase chain reaction methods. Results The genotypes 677TTof the MTHFR gene, 936TT, 936CT, and 634CC, 634GC of the VEGF gene, and allele 894Tof the NOS3 gene were associated with a predi position to RPL in the Russian population. A significant role of additive and epistatic effects in the gene–gene interactions of the SNPs of SERPINE-1, ACE, NOS3, MTHFR, and VEGF genes in RPL was demonstrated. Conclusions The results showed that gene–gene interactions are important for RPL susceptibility. Additionally, analysis of the genotype combinations of several allelic variants provides more information on RPL risk than analysis of independent polymorphic markers.