Identification of single nucleotide polymorphisms in the p21 (CDKN1A) gene and correlations with longevity in the Italian population

Abstract

Longevity in humans is determined by multiple environmental and genetic factors. We have investigated possible associations between longevity and Single Nucleotide Polymorphisms (SNPs) in the p21 (CDKN1A) gene, a stress-inducible senescence-associated cell cycle inhibitor, expression of which upregulates genes implicated in several age-related diseases. By sequencing the promoter and exons of p21 in genomic DNA of ten individuals over 90 years old, we have identified 30 SNPs, many of which had not been previously characterized. A cluster of minor alleles within the -4547/-3489 bp region did not alter the basal activity or p53 responsiveness of the p21 promoter. We then compared the frequency of 41 p21 SNPs between 184 centenarians and 184 younger subjects in the Italian population. Rare alleles of two exon-derived SNPs, rs1801270 and rs1059234, were significantly under-represented among the centenarians; no significant differences were found for 39 non-exonic SNPs. SNP rs1801270 causes Ser to Arg substitution at amino acid 31 and SNP rs1059234 leads to a nucleotide change in the 3'-untranslated region. Previous studies showed that the rare alleles of these two SNPs may play a role in cancer. These p21 alleles may be potentially detrimental to longevity and therefore are rare in centenarians.

Demographic characteristics of Sardinian centenarian genealogies: Preliminary results of the AKeA2 study

“…We regard this result as very important, particularly in relation to the many results recently obtained in genetics. All the data collected in this and other studies suggest that, as well as a variety of nuclear DNA polymorphisms (Di Bona et al 2009;Gravina et al 2009;Invidia et al 2010;Lescai, Marchegiani, and Franceschi 2009;Salvioli et al 2006;Testa et al 2009), maternally inherited mitochondrial DNA variants (Capri et al 2008;Raule et al 2007;Rose et al 2007;Rose et al 2010;Santoro et al 2006) contribute substantially to human longevity too.…”

P21 Gene Variation and Late-Onset Alzheimer’s Disease in the Italian Population

“…The frequencies we obtained in the control sample agree with those reported in the literature for Europeans. For the Italian population, in particular, we could compare the trend of our frequencies with those obtained by Gravina et al [32] in a study concerning the distribution of P21 allele and genotype frequencies in a sample of healthy long-lived individuals and in a sample of controls. Although we could only compare the control groups, we ascertained that the allele distributions were similar to those observed by these authors.…”

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

“…Furthermore, it is noteworthy that the CDKN1A gene is located on chromosome 6 in relative proximity to MHC class I genes, some of which are significantly associated with the elite controller phenotype (10,30). Although we did not observe any relationship between p21 expression intensity in CD4 + T cells and protective HLA alleles, such as HLA-B57 and HLA-B27, it remains to be determined in larger studies whether MHC class I gene polymorphisms associated with better HIV-1 disease outcomes are linked to specific mutations in the CDKN1A gene (31,32) that may affect its expression. Moreover, the transcription factor Foxo3A, which may be involved in the regulation of CDKN1A gene expression, is uniquely expressed in CD4 + T cells from elite controllers (33), and it will be important to analyze whether it participates in the epigenetic control of high-level p21 expression in such cells.…”