title: Germline genetics of the p53 pathway affect longevity in a gender specific manner.
abstract: Aging is thought to occur through the accumulation of molecular and cellular damage. A key regulator of the cell's stress response is p53. In mice, the activity of p53 associates with lifespan. We were therefore interested whether SNPs in members of the p53-pathway are associated with longevity in humans. We genotyped the following SNPs: p53 - rs1042522 (Arg72Pro), MDM2 - rs2279744 (SNP309), MDM4 - rs4245739 (SNP34091), rs1563828 (SNP31826), PPP2R2B (rs319217) in 155 long-lived individuals (LLIs) who died at the age of 91 and over and in 171 ethnically-matched control subjects. Kaplan-Meier survival curves and log-Rank-test were used to determine the mean and median survival times. In female LLIs, the Pro-allele of rs1042522 (Arg72Pro) and the G-allele of rs2279744 (SNP309) were significantly associated with an increased survival time (P=0.026, P<0.001, respectively, log-Rank-test). In contrast, there was no difference regarding the survival time in male LLIs (rs1042522: P=0.58, rs2279744: P=0.503, log-Rank-test). There was no difference regarding the average age of death for the genotypes of the respective SNPs in the MDM4 gene (rs1563828: P=0.99; rs4245739: P=0.179, respectively). Here we show for the first time that the G-allele of rs2279744 (SNP309) is associated with increased lifespan. Importantly, this effect is gender-specific. Our data support the hypothesis that genetic variants that are associated with lower activity of p53--and therefore increased tumor risk--are associated with prolonged lifespan in a gender-specific manner.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Groß
authors.forename: Uta-Dorothee
authors.initials: UD
authors.lastname: Immel
authors.forename: Michael
authors.initials: M
authors.lastname: Klintschar
authors.affiliation: Institute of Pathology, Faculty of Medicine, University of Halle-Wittenberg, Magdeburger Str. 14, D- 06097 Halle/Saale, Germany. frank.bartel@medizin.uni-halle.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Bartel
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008136:Longevity / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054648:Protein Phosphatase 2 / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012737:Sex Factors; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C505936:PPP2R2B protein, human; D054648:Protein Phosphatase 2