| The incidence rate of infertility has been on the rise, about10-15%couples face the inability to get pregnant. In short, infertility/sub-fertility has become a global social problem. After endeavor during the past30years, the current success rate only hovers around30-40%. Except for the age factor, no other predicting markers of pregnancy are found. Thus, the study from multiple perspectives on the failure of implantation has become the focus of the study. Successful implantation of the embryo in the uterus is the key to a successful pregnancy after an A.R.T. treatment. In addition to environmental factors, genetic factors have also become the focus of studies by many researchers.It was found that P53tumor suppressor gene plays an important role in embryo implantation of experimental animals recently. As a transcription factor, TP53can take part in the cell cycle regulation, genome stability, cell differentiation and apoptosis by regulating the expression of some genes. TP53has a functional polymorphism, the G>C change at codon72, which results in Arg>Pro amino acid substitution, which changed the biological activity of P53protein. Studies suggested that TP53codon72is associated with infertility, endometriosis and LIF expression levels in intrauterine. MDM2is one of the important negative regulate factors of TP53. Its functional polymorphism MDM2SNP309is involved in the biological activity change of MDM2protein. In-depth studies found that there are correlation between the tumor of some tissues and organs and missed abortion.Human embryonic implantation process is regulated by the female reproductive endocrine. It was found that FSH/LH ratio play an important role in the course of IVF therapy. The first phenomenon of ovarian function decline is the raise of FSH than LH, but the FSH rose higher and earlier than LH. So the ratio of FSH/LH is more valuable than simple FSH to predicting ovarian function. While mainly egg quality rather than quantity decrease at first, it is uncertain that FSH/LH ratios predict IVF treatment outcome.As a multiple effect of cell factor, LIF in follicular fluid are closely related to the development of oocyte and ovulation. It was not sure whether LIF levels of follicular fluid are associated with individual genotype and pregnancy outcome.In order to find the influence factors of infertility and IVF outcome we performed the research from the perspective of genetic, hormonal, and cytokines.We performed this study to elaborate the relationship of TP53codon72and MDM2SNP309with male and female infertility by analysis the distribution of gene polymorphism. To draw the association of clinical pregnancy outcome with LIF levels in follicular fluid, we examined the concentration of LIF in follicular fluid. We look for the predicting marker of clinical pregnancy by examining the basal FSH/LH ratio.DNA samples from a total of1450infertile female patients performing IVF-ET treatment and250fertile female,483infertile male patients and401fertile male, were collected from The Second Hospital affiliated Kunming Medical College from September2009to September2012. Genotypes determination were tested by PCR-RFLP method.326follicular fluid samples from IVF-ET patients were collected to used for checking LIF concentration, ELISA method was used to examine the LIF levels in follicular fluid;1051day3serum samples were collected to examine basal FSH and LH levels; chemical luminescence immunoassay was used to determine the concentration of FSH and LH.The distribution frequency of TP53code72Pro/Pro, Pro/Arg and Arg/Arg in female infertility and control population were23.52%vs.20.80%,51.52%vs.53.20%and24.97%vs.26.00%individually, the results showed the allele Pro was not the risk factor of infertility (OR=1.08,95%CI:0.79-1.31, p=0.44); The distribution frequency of Pro/Pro genotype in endometriosis and control were28.10%vs.20.08%, it showed that the genotype of Pro/Pro increase the risk occurring endometriosis (OR=1.56,95%CI:1.02-2.53, p<0.05).The frequency of allele Pro was52.10%vs.47.40%in patients with positive and negative pregnancy outcomes, it decreased the risk of pregnancy failure(OR=0.83,95%CI:0.71-0.96, p=0.01). The distribution frequency of MDM2SNP309polymorphism genotype T/T, T/G and G/G were22.08%vs.18.40%,54.55%vs.55.60%and23.38%vs.16.00%in infertility and control population, the results showed the allele T was not the risk factor of female infertility(OR=1.06,95%CI:0.81-1.34, p=0.31). The distribution frequency of T allele were54.00%vs.46.90%in patients of polycystic ovary syndrome and control population, it increased the risk of polycystic ovary syndrome (OR=0.83,95%CI: 0.71-0.96,p=0.01). The frequency of MDM2SNP309T allele was49.60%vs.48.10%in patients with positive and negative pregnancy outcome, T allele did not increase the risk of pregnancy failure(OR=0.93,95%CI:0.82-1.14,p=0.41). Due to effect of age on the infertility and pregnancy outcome, we performed the stratification analysis about the association of the polymorphisms of TP53code72SNP and MDM2SNP309with the infertility and pregnancy outcome by age, which showed no obvious effect.The distribution frequency of TP53code72Pro/Pro, Pro/Arg and Arg/Arg in male infertility and control population were28.90%vs.22.40%,42.20%vs.53.40%and28.90%vs.24.20%individually, the results showed that the allele Pro do not increase the risk of male infertility(OR=1.04,95%CI:0.74-1.45, p=0.84). The distribution frequency of MDM2SNP309polymorphisms T/T, T/G and G/G in female infertility and control were20.50%vs.23.80%,57.80%vs.54.19%and21.70%vs.21.91%, allele T did not increase the risk of female infertility(OR=1.01,95%CI:0.76-1.80,p=0.71). When we analyzed the combination of the polymorphism of TP53codon72SNP and MDM2SNP309, the results showed that the joint genotype Pro/ProG/G had lower pregnancy rate than mean rate of other genotypes(27.91%vs.39.27%,p=0.03), genotype Arg/Arg G/G added the risk of pregnancy failure. It was not obvious that the age effect on the association of polymorphism of these two genes with male infertility and IVF pregnancy outcome in our stratified analysis.In China population of young patients(<35years)with normal basal FSH(<10IU/L)undergoing IVF-ET treatment were studied. Patients with FSH/LH<2has significant higher pregnancy rate than the patients with FSH/LH>2(47.53%vs.38.65%, p=0.04). The combination of FSH/LH<2and TP53codon72Pro decreased the risk of IVF pregnancy failure(OR=0.75,95%CI:0.62-0.91, p=0.01). There was no correlation between polymorphism of MDM2SNP309and the different IVF outcomes under different FSH/LH ratio.In summary, the results of association between polymorphisms of TP53codon72SNP and MDM2SNP309and the infertility and IVF outcomes showed there was association between TP53codon72polymorphism and endometriosis and IVF pregnancy outcome; MDM2SNP309polymorphism and polycystic ovary syndrome; Arg/Arg G/G genotype and IVF outcome; FSH/LH<2and the conjunction of FSH/LH<2with TP53codon72Pro allele and IVF pregnancy outcome. For the limited samples, candidate gene and other environmental factor, more studies of pregnancy mechanism and screening examination with large samples and more race population under different region should be done. |
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