TP53*P72 allele negatively affects female life expectancy in a population of Central Italy according to a cross-sectional study and genetic-demographic analysis. The study aimed to investigate the association of TP53 P72R (rs1042522) with longevity in a population of Central Italy (18106 years, n = 1,072) by considering demographic information and frequency data to account for different survival rates between sexes through applying a genetic-demographic approach. The results showed that rs1042522 affects female longevity, being 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 study suggests that 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.The frequencies are statistically significant (OR 0.586; 95% CI 0.420-0.817; p = .002). The TP53*P72 allele was considered the risk allele due to previous associations found between the *P72 allele and enhanced survival in Dutch and Swedish long-lived people. In men, there is no significant difference between the survival functions of carriers (SA(x)), noncarriers (SB(x)), and the male population (S(x)) (p = .930), but in this case, no crossing of the survival curves was observed, suggesting no association of this polymorphism with survival in the male sample. Statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL). Two-tailed probability values of less than .05 were regarded as statistically significant. Bonferroni's correction for multiple testing was not performed since we are assessing specific questions on a gene previously tested for association with human longevity, and we are not searching for associations without a priori hypotheses (16).

During the last 20 years, rs1042522 has been extensively studied, and numerous findings have been proven effective and relevant for some pathogenic mechanisms underlying common phenotypes and life-threatening diseases. However, its role in aging and longevity still raises several questions and conflicting results. Here, we provide novel evidence for rs1042522 in longevity; in the Central Italy population we studied, the TP53*P72 allele influences negatively female life expectancy. We did not detect any association of rs1042522 with longevity in men, a finding consistent with previous studies conducted in Italian (cross-sectional study) and Ashkenazi (case-control) populations (7,8). In contrast to our results, the follow-up study on the cohort of 9,219 participants aged 20-95 years from the Danish general population by Ørsted and colleagues (9) demonstrated an increased frequency of P*/P* homozygotes and the TP53*P72 allele with increasing age toward 90 years. A similar result was obtained in the prospective Leiden 85-plus follow-up study that reported a 1.41-fold increase in survival of carriers of the P*/P* genotype compared with R*/R* carriers (p = .032 [10]). However, contrary to the study of Ørsted and colleagues (9), no survival benefit was noticed for the R*/P* genotype, survival being 0.95-fold lower (p = .550 [10]). Both longitudinal studies (9,10) used gender-adjusted hazard ratios, whereas the Italian cross-sectional study (7) was conducted on the whole population enrolled without stratifying by gender.

Results: The allele and genotype frequency distributions of rs1042522 were compared among the age classes, men and women separately (Table 1). No significant deviation from Hardy-Weinberg Equilibrium expectation was detected among the gender-specific age classes. The genotype distribution and allele frequency in Age Class 1 (women + men) are comparable to that previously reported for the Italian population (p > .205 [6]). Therefore, the sample can be considered a representative sample of the continental Italian population. Rs1042522 affects female longevity, showing significant associations in Comparison 2 (Age Class 3 vs Age Class 2) under both additive (common OR 0.574; p = .006) and dominant (OR 0.513; 95% CI 0.317-0.830; p = .006) genetic models (Table 1). The P72* allele is significantly underrepresented in Age Class 3 only in women (Comparison 2: allele, OR 0.575; 95% CI 0.381-0.866; p = .008).

As the GD method requires the assumption of dominance of one allele over the other, a P72* > R72* dominant relationship was assumed. Figure 1 shows the maximum likelihood estimates of the survival functions of TP53*P72 carriers (P*/P* plus P*/R*) participants (blue curve) and R*/R* participants (red curve), compared with the general Italian population (green curve). Panel A shows the female population, whereas panel B shows the male one.