Gravina Silvia, Lescai Francesco, Hurteau Gregory, Brock Graham J, Saramaki Anna, Salvioli Stefano, Franceschi Claudio, Roninson Igor B
Cancer Center, Ordway Research Institute, Albany, NY 12211, USA.
Aging (Albany NY). 2009 May;1(5):470-80. doi: 10.18632/aging.100041.
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.
人类的长寿由多种环境和遗传因素决定。我们研究了长寿与p21（CDKN1A）基因中的单核苷酸多态性（SNP）之间的可能关联，p21是一种应激诱导的衰老相关细胞周期抑制剂，其表达上调与几种年龄相关疾病有关的基因。通过对10名90岁以上个体的基因组DNA中的p21启动子和外显子进行测序，我们鉴定出30个SNP，其中许多以前未被表征。-4547 / -3489 bp区域内的一组次要等位基因不会改变p21启动子的基础活性或p53反应性。然后，我们比较了意大利人群中184名百岁老人和184名年轻受试者之间41个p21 SNP的频率。两个外显子衍生SNP（rs1801270和rs1059234）的罕见等位基因在百岁老人中的代表性明显不足；39个非外显子SNP未发现显著差异。SNP rs1801270导致氨基酸31处的丝氨酸被精氨酸取代，SNP rs1059234导致3'非翻译区的核苷酸变化。先前的研究表明，这两个SNP的罕见等位基因可能在癌症中起作用。这些p21等位基因可能对长寿有潜在的不利影响，因此在百岁老人中很少见。
