TP53*P72 Allele Influences Negatively Female Life Expectancy in a Population of Central Italy: Cross-Sectional Study and Genetic-Demographic

Fabio Di Pietro,1 Serena Dato,2 Francesco M. Carpi,1 Jason J. Corneveaux,3,4 Simona Sebastiano Maoloni,5 Fiorenzo Mignini,6 Matthew J. Huentelman,3,4 Giuseppe Passarino,2 and Valerio Napolioni1,3

Downloaded from http://biomedgerontology.oxfordjournals.org/ at Univ of Iowa-Law Library on August 8, 2015

6School of Pharmacy and Health Products, University of Camerino, Camerino,

Address correspondence to Valerio Napolioni, PhD, School of Biosciences and Biotechnologies, Via Gentile III da Varano, University of Camerino, 62032 Camerino, Italy. Email: valerio.napolioni@unicam.it

The association of TP53 P72R (rs1042522) with longevity remains uncertain and varies with ethnicity. Here, we its association with longevity in a cross-sectional population of Central Italy (18–106 years, n = 1,072), by ing demographic information and frequency data to account for the different survival rates between sexes through application of a genetic-demographic approach. rs1042522 affects females longevity, showing significant in Comparison 2 (Age Class 3 [>91 years] vs Age Class 2 [73–91 years]) under both additive (odds ratio [oR] p = .006) and dominant (oR 0.513; p = .006) models. The TP53*P72 allele is significantly underrepresented in Age 3 only in women (oR 0.575; p = .008). The genetic-demographic approach demonstrated that the frequency of TP53*P72 carriers underwent a significant reduction after 82 years (oR 0.586; p = .002). The same analyses gave significant results in men. The discrepancies among the results obtained on rs1042522 for longevity could result from pleiotropic effects of p53 and the potential ethnic variation of its functional variants.

Key Words: p53—Polymorphism—Gender—Longevity.

Received June 8, 2012; accepted october 2, 2012

editor:Placido navas, PhD

ing apoptosis and suppressing cellular transformation and has a lower transcriptional activity toward a subset of p53 target genes involved in apoptosis and DNA repair com- pared with the TP53*R72 allele (5). Thus, in light of the striking impact of rs1042522 on p53 function, several studies have been undertaken to address its role in longev- ity with inconsistent results. No significant differences in rs1042522 distribution were detected in various age classes of Italian centenarians (6,7) and in the Ashkenazi popula- tion (8), as well. However, studies of Swedish and Dutch long-lived people, which included follow-up, revealed that the P72* allele was associated with an enhanced capacity to survive (9,10). Intriguingly, rs1042522 frequencies cor- relate with latitude but are similar in ethnic groups dwelling in the same geographical regions. This finding led to the hypothesis that they may be involved in climatic adaptation (11) and provide a potential explanation for the association

locus 17p13.1, OMIM*191170) is the main determi- nant of cellular stress responses and regulates target genes inducing cell cycle arrest, apoptosis, senescence, DNA repair, and/or metabolic changes. Mutation of TP53 is one of the most frequent oncogenic events in human cancer. Moreover, TP53 has been involved in organismal aging (1,2). Gain-of-function TP53 mutations have been linked not only to a reduced frequency of tumors but also to accel- erated aging and premature death in mice (3). This evidence supports the view that TP53 could be considered a gene that affects human longevity.

A functional nonsynonymous single nucleotide poly- morphism located in exon 4 of the TP53 gene (rs1042522), leading to a P72R substitution, has been extensively stud- ied in reference to several diseases, from cancer to schizo- phrenia (4). Marked functional differences exist between the two forms of the p53 protein (4); it has been reported

5ʹ–TGCTCTTTTCACCCATCTAC–3ʹ and 5ʹ–CGTGCAA GTCACAGACTT–3ʹ (Sigma-Aldrich, MO). An initial denaturation at 95°C for 9 minutes was followed by 40 cycles of denaturation at 94°C for 30 seconds, annealing at 61°C for 30 seconds, and extension at 72°C for 30 seconds, with a final extension at 72°C for 4 minutes. PCR prod- ucts (301 bp) were digested at 60°C for 3 hours with BstUI (NEB). Restriction fragments were visualized on 2% aga- rose gel electrophoresis with ethidium bromide staining and genotypes were assigned as previously reported (13). Each sample was genotyped in duplicate with a positive control. DNA sequencing was performed on 40 random samples showing 100% concordance with PCR–RFLP method.

between the polymorphism and longevity being found only in populations living in northern geographic areas.

studies in genetic epidemiology and the marked differences of genotype frequency distribution among ethnic groups, we attempt to replicate previous findings by testing the association of rs1042522 with longevity in a healthy population of Central Italy through a cross-sectional study, by applying a genetic-demographic (GD) approach that takes into account the demographic information and different survival rates between sexes for modeling the survival of specific allele carriers in the population.

from http://biomedgerontology.oxfordjournals.org/ at Univ of Iowa-Law Library on August 8, 2015

Methods

Demographics

GD approach