The common germline Arg72Pro polymorphism of p53 and increased longevity in humans
The common germline Arg72Pro polymorphism of p53 and increased longevity in humans
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DOI：
10.4161/cc.7.2.5249
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发表时间：
2008-01-15
期刊：
影响因子：
4.3
通讯作者：
Nordestgaard, Borge G.
中科院分区：
文献类型：
--
作者：
Bojesen, Stig E.;Nordestgaard, Borge G.
在人类中已经发现了超过一千万个单核苷酸多态性（SNP）;然而，大多数SNP对健康和疾病的重要性尚不清楚。大多数SNP确实是不重要的，而且由于研究的动力不足，许多关于SNP效应的观察结果无法被其他研究人员重复。SNPs最多只能影响蛋白质的功能或水平，很少影响疾病的风险，几乎从来不会影响最终终点的总死亡率。肿瘤抑制基因TP 53中的一个众所周知的功能性SNP导致寿命延长：在丹麦普通人群（n = 9219）中，次要等位基因的纯合子与主要等位基因的纯合子相比，中位生存期延长3年。这部分地解释为癌症或其他疾病发展后存活率增加，这与p53蛋白中的Arg 72 Pro取代通过增加细胞凋亡对细胞死亡具有重要影响的观察结果一致。因此，增加的寿命可能是由于在诊断出任何危及生命的疾病后普遍增加的稳健性。与对SNP在人类中的重要性的广泛怀疑相反，这种对细胞修复机制具有重要性的功能获得性p53 SNP对寿命具有深远的影响。
More than ten million single nucleotide polymorphisms ( SNPs) have been identified in humans; however, the importance of most SNPs for health and disease is not understood. Most SNPs are indeed unimportant and because of often inadequately powered studies, many observations on SNP effects can not be repeated by other researchers. SNPs are at best shown to influence protein function or level, rarely to influence risk of disease, and almost never to influence total mortality, the ultimate endpoint. A well-known functional SNP in the tumor suppressor TP53 gene leads to increased longevity: in the Danish general population (n = 9219) homozygotes for the minor allele versus homozygotes for the major allele had an increase in median survival of 3 years. This is partly explained by increased survival after development of cancer or other diseases, in accordance with the observation that this Arg72Pro substitution in the p53 protein has important influence on cell death via increased apoptosis. Thus, the increased longevity may be due to a generally increased robustness after a diagnosis of any life-threatening disease. In contrast to widespread skepticism on the importance of SNPs in humans, this gain-of-function p53 SNP of importance for cell repair mechanisms has a profound influence on longevity.