Influência dos polimorfismos TP53 (rs1625895), TP73 (rs3765730), MMP9 (rs17576) e MTHFR (rs868014) na classificação da reserva ovariana em pacientes inférteis

Abstract

Among all the challenges to be overcome by physicians and patients in IVF/ICSI treatments, we can highlight the high variability and the difficulty in predicting the ovarian response after the use of gonadotrophins in different stimulation protocols. The criteria such as age, anti-mullerian hormone (AMH) and antral follicle count (AFC) had been employed to assist physicians in the individualization of ovarian stimulation protocols for assisted reproduction cycles. Although these parameters are widely used to predict ovarian reserve, we often do not have a significant predictive value. This variability may be due to genetic predispositions of single nucleotide polymorphisms (SNPs). Objective: To investigate the influence of TP53 (rs1625895), TP73 (rs3765730), MMP9 (rs17576) e MTHFR (rs868014) polymorphisms in the classification of ovarian reserve in infertile patients. Casuistics and Method: A cross-sectional study was carried out in 145 infertile women who underwent infertility evaluation in the Assisted Reproduction Centers involved. All of the recruited women met the following inclusion criteria: age ≤37 years, body mass index between 20-30 kg/m2, regular menstrual cycle, ultrasound evidence of the two ovaries and no ovarian surgery, no endometriosis, no hydrosalpinx, infections or endocrine problems. Peripheral blood sample from each patient was used to measure anti-Müllerian hormone using the Beckman Coulter Inc (GenII) kit and to genotype the TP53T>C (rs1625895), TP73G> A (rs3765730), MMP9Gln>Arg (rs17576) and MTHFRA>G (rs868014) polymorphisms. The antral follicle count was performed by transvaginal ultrasonography. Fisher's exact test was used to compare the categorical variables. For the comparison of continuous variables with normal distribution, the Student's t test was used and for those without normal distribution, the Mann-Whitney test was used. In addition, odds ratio analysis was used to determine the association of each polymorphism in the prediction of low ovarian reserve. The alpha value adopted was 5%. Results: Two groups were selected by different dosages of AMH and AFC: 86 women were characterized as being low ovarian reserve (LOR) (AMH <1ng/mL + AFC ≤9) and 59 as normal ovarian reserve (NOR) (AMH >2ng/mL + AFC ≥15). After this classification, we compared the two groups (LOR X NOR) in relation to the genotypes of each polymorphism studied. Women characterized as LOR presented higher incidence of the following genotypes: TP53-T/T; TP73-G/G; MMP9-Gln/Gln and MTHFR-A/A. Conclusions: The presence of the TP53-T/T, TP73-G/G, MMP9- Gln/Gln and MTHFR-A/A genotypes increases, respectively in 3.5 / 2.5 / 3.0 / 3.6-fold in the chance of the woman presenting LOR. In addition, the association of the TP53- T/T + TP73-G/G genotypes increases in 4.7-fold the chance of the woman presenting LOR. Therefore, these polymorphisms can be used as an additional tool to classify the ovarian reserve.