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

Kang, H. J., Feng, Z., Sun, Y., Atwal, G., Murphy, M. E., Rebbeck, T. R., Rosenwaks, Z., Levine, A. J., Hu, W. (2009) Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci U S A, 106 (24). pp. 9761-6. ISSN 1091-6490 (Electronic)0027-8424 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/19470478
DOI: 10.1073/pnas.0904280106

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.

Item Type: Paper
Uncontrolled Keywords: Alleles Codon Embryo Implantation Fertility/ genetics Fertilization in Vitro Humans Leukemia Inhibitory Factor/physiology Polymorphism, Single Nucleotide Tumor Suppressor Protein p53/ genetics
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > SNP
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
organism description > animal > mammal > primates > hominids > human
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL labs > Atwal lab
Depositing User: Matt Covey
Date Deposited: 19 Feb 2013 16:38
Last Modified: 08 Nov 2017 20:47
PMCID: PMC2700980
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27454

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