Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans

Abstract

The tumor suppressor protein p53 plays an important role in maternal reproduction in mice through transcriptional regulation of leukemia inhibitory factor (LIF), a cytokine crucial for blastocyst implantation. To determine whether these observations could be extended to humans, a list of single-nucleotide polymorphisms (SNPs) in the p53 pathway that can modify the function of p53 was assembled and used to study their impact on human fertility. The p53 allele encoding proline at codon 72 (P72) was found to be significantly enriched over the allele encoding arginine (R72) among in vitro fertilization (IVF) patients. The P72 allele serves as a risk factor for implantation failure. LIF levels are significantly lower in cells with the P72 allele than in cells with the R72 allele, which may contribute to the decreased implantation and fertility associated with the P72 allele. Selected alleles in SNPs in LIF, Mdm2, Mdm4, and Hausp genes, each of which regulates p53 levels in cells, are also enriched in IVF patients. Interestingly, the role of these SNPs on fertility was much reduced or absent in patients older than 35 years of age, indicating that other functions may play a more important role in infertility in older women. The association of SNPs in the p53 pathway with human fertility suggests that p53 regulates the efficiency of human reproduction. These results also provide a plausible explanation for the evolutionary positive selection of some alleles in the p53 pathway and demonstrate the alleles in the p53 pathway as a good example of antagonistic pleiotropy.

Fig. 1.

The regulation of LIF expression levels by p53 with different SNPs at codon 72. Human melanoma cell lines homozygous for R72 (WM115, gray bar) and homozygous for P72 (WM278, black bar) were irradiated with 5 Gy of gamma-IR. The RNA expression levels of LIF were measured at 16 h after IR by real-time PCR. All values were normalized to the levels of β-actin, and the averages of 3 independent experiments are represented. con, control.

Fig. 2.

Implantation rate and pregnancy rate after IVF in young patients with infertility carrying different genotypes at p53 codon 72. Implantation rate was calculated as gestations sacs/embryo transferred. A serum hCG level >5 mIU/mL at 9–11 days after embryo transfer was defined as a successful pregnancy. Clinical pregnancy rate is defined as fetal cardiac activity detected by transvaginal ultrasound at 6–7 weeks of gestation. p53 P72 was associated with a significantly lower implantation rate (A), pregnancy rate (B), and clinical pregnancy rate (C). Arg, arginine; Pro, proline.

Fig. 3.

Haplotype structure of the Hausp gene in African-American and Caucasian populations. (A) Schematic diagram of the Hausp gene and the SNPs genotyped for the study of haplotype structure. (B and C) Inferred haplotype frequencies in African-American and Caucasian populations, respectively. dbSNP, data base-SNP; ID, identification; rs, reference sequence.

Fig. 4.

SNPs in p53 and the p53 pathway associated with human fertility. Naturally occurring polymorphisms in the p53 pathway listed in the diagram, which modify the function of the p53 pathway, could have an impact on human fertility.