Genetic-epigenetic aspects of infertility in women with long-COVID-19

Abstract

The aim of the study is to determine the genetic and epigenetic features of infertile patients with long-term COVID-19 in order to clarify the risk factors for the failure of assisted reproductive technologies (ART) use. Materials and methods. The MTHFR (C677T, A1298С), RFC-1 (G80A) and BHMT (G742A) gene polymorphisms and the methylation of ESR1 gene was performed. 40 patients (main group) with infertility due to long-term COVID-19 were examined: the subgroup 1 - 25 women in whom the use of ART was ineffective, the subgroup 2 - 15 patients with effective use of ART. The control was taken from literary sources: for RFC (G80A), MTHFR (C677T) and MTHFR (A1298C) polymorphisms - 35 Ukrainian women without infertility and reproductive losses; for BHMT (G742A) - 60 people of the Ukrainian population. The methods of variational statistics were used, in particular the Fisher test with a significance level of p<0.05. Results. Patients of the main group have a higher frequency of the homozygous genotype of the MTHFR gene polymorphism (C677T) on the mutant T allele (20.0% vs. 3.2%; p<0.05). When ART is unsuccessful, the TT genotype is 4 times greater (28.0% vs. 6.7%; p<0.05). A study by genotypes of MTHFR polymorphism (A1298C) did not reveal a significant difference. Patients of the main group `have a higher frequency of the mutant allele A of the RFC gene (G80A) (80.0% vs. 51.4%; p<0.05). No significant difference was found depending on the success rate of ART. The frequency of BHMT gene polymorphism (G742A) in the main group did not differ from that in the Ukrainian population, however, in the case of unsuccessful ART, it was observed less often and only in the heterozygous variant (40.0% vs. 66.6%; p<0.05). The analysis of pairwise intergenic interaction revealed the highest frequency of the combination of AAGA for the MTHFR (A1298C)+BHMT (G742A) pair - 35.0% and GAAA for the RFC (G80A)+MTHFR (A1298C) pair - 30.0% in the main group. Hypermethylation of the promoter region of the ESR1 gene is observed in 20 (50.0%) patients of the main group: in 17 (68.0%) women of the subgroup 1 versus 3 (20.0%) women of the subgroup 2 (p<0.05). Conclusions. The genetic and epigenetic conditioning of the success of ART programs in infertility associated with long-term COVID-19 has been revealed, which opens up new diagnostic and therapeutic opportunities for identifying factors predisposing to unsuccessful ART treatment and increasing the effectiveness of such treatment by correcting disorders of folic acid metabolism, hyperhomocysteinemia and the estrogens receptor apparatus. The research was carried out in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Local Ethics Committee of the institution mentioned in the work. Informed consent of the women was obtained for the research. The authors declare no conflict of interest.