The role of polymorphisms in the genes of the hemostasis system and the folate-methionine cycle in the development of recurrent pregnancy loss

Abstract

BACKGROUND: Recurrent pregnancy loss is a serious clinical problem that complicates about 2% of pregnancies. There is evidence that thrombophilia and disorders of folate-methionine metabolism may cause recurrent pregnancy loss.

AIM: The aim of this study was to evaluate the contribution of polymorphic variants of the genes of the hemostasis system and the folate-methionine cycle in women with recurrent pregnancy loss.

MATERIALS AND METHODS: Clinical examination of 406 pregnant women divided into two study groups was carried out. The main study group consisted of 206 women with two or more pregnancy losses known up to 12 weeks of pregnancy; the control group included 200 apparently healthy women with a known history of two or more live births, no spontaneous or induced abortions, infertility, or endometriosis. All patients underwent a molecular genetic study of 12 single nucleotide polymorphisms in the genes of the hemostasis system and the folate-methionine cycle performed by real-time polymerase chain reaction.

RESULTS: We studied single nucleotide polymorphisms in eight genes involved in the hemostasis system and in four genes of the folate-methionine cycle. An association of presence of alternative variants such as 1565C (rs5918) of the ITGB3 integrin beta-3 gene and A66G (rs1801394) of the MTRR methionine synthase reductase gene with the development of recurrent pregnancy loss was found. The frequency of their occurrence was 29.1 and 77.7% in the recurrent pregnancy loss group vs. 12.0 and 49.0% in the control group, respectively (p < 0.01). The combined carriage of the alternative variants 1565C (rs5918) of the ITGB3 gene and A66G (rs1801394) of the MTRR gene in the recurrent pregnancy loss group was diagnosed more often than in the control group and amounted to 47 (22.8%) vs. 12 (6.0%) cases (φ = 5.047; p < 0.01; odds ratio 3.631; 95% confidence interval 2.374–9.034). We have thus developed a three-locus model of the synergetic action of allelic variants of the above genes in the development of recurrent pregnancy loss in early pregnancy [10976 G>A (rs6046) of the F7, −455 G>A (rs1800790) of the FGB, 1565 T>C (rs5918) of the ITGB3] with reproducibility of 8/10, sensitivity of 65.6%, and specificity of 68.8% (χ² = 15.7415, p < 0.0001; odds ratio 3.341, 95% confidence interval 1.824–6.118).

CONCLUSIONS: This study allows for confirming the hypothesis that the status of genetic variants of the ITGB3 and MTRR genes and the association of three single nucleotide polymorphisms: rs6046 of the F7, rs1800790 of the FGB, and rs5918 of the ITGB3 may be used as predictors of recurrent pregnancy loss development.

Keywords

recurrent pregnancy loss / single nucleotide polymorphism / integrin beta-3 gene / methionine synthase reductase gene

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