The G->c polymorphism of the p53 gene is strongly associated with decreased pregnancy rates in fresh IVF patients via an ovarian mechanism

Abstract

OBJECTIVE: p53 is a key tumor suppressor gene responsible for the repair of damaged DNA. A polymorphism of the p53 gene at codon 72 (Arg→Pro) decreases p53 activity and may lead to an increase in DNA damage during oogenesis. Protein products of the p53 gene have also been shown to promote leukocyte inhibitory factor (LIF) production in the murine model and its reduction in p53 null mice significantly decreases litter size. We hypothesize that women who carry the p53c72 (pro/pro) polymorphism of the p53 gene may experience decreased implantation rates, either through diminished LIF production at the level of the endometrium or through diminished oocyte quality from inadequate DNA repair mechanisms. DESIGN: Prospective analysis of oocyte donor recipients and young women (<35) with unexplained infertility. Incidence of the p53c72 Pro (variant) polymorphism compared to p53c72 Arg (wild type) was assessed as well as IVF outcome. MATERIALS AND METHODS: A total of one hundred and sixty three samples were collected from donor egg recipients (DER) (n=76) and patients <35 years of age (n=87) with unexplained infertility. DNA was extracted and polymerase chain reaction amplification of p53c72 was performed. The frequency of each variant was compared to known population controls. Oocyte yield, implantation rates, and pregnancy rates were analyzed. RESULTS: The prevalence of the variant polymorphism was increased in our infertile population compared to the general population (47% vs. 35%, p<0.05). In the DER group, there was no difference in average age, implantation rates (52% vs. 48%) or pregnancy rates (78% vs. 85%) for patients with the variant polymorphism compared to the wild type, respectively. In the fresh IVF group, there was no difference baseline characteristics, however, within this group those with the polymorphism indicating lower p53 activity had decreased oocyte yield (9.31± 4.1 vs.12.8±5.3, p<0.05), decreased implantation rates (16% vs. 44%, p<0.01), and decreased pregnancy rates 30% vs.68% p<0.01) compared to the wild type. CONCLUSIONS: We have found that women who are homozygous for the p53c72Pro variant have both a decreased ovarian response to exogenous gonadotropins and decreased pregnancy rates when compared to the wild type. This suggests that p53 activity is crucial to oogenesis and early embryogenesis. The lack of impact of p53 activity on the DER population suggests that other cytokines may help overcome any negative impact of this polymorphism at the level of the endometrium.