The common germline Arg72Pro polymorphism of p53 and increased longevity in humans Stig E. Bojesen & Børge G. Nordestgaard Published online: 04 Feb 2008.

To cite this article: Stig E. Bojesen & Børge G. Nordestgaard (2008) The common germline Arg72Pro polymorphism of p53 and increased longevity in humans, Cell Cycle, 7:2, 158-163, DOI: 10.4161/cc.7.2.5249

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The common germline Arg72Pro polymorphism of p53 and increased longevity in humans

Stig E. Bojesen* and Børge G. Nordestgaard

Department of Clinical Biochemistry; Herlev Hospital; Herlev, Denmark; Copenhagen University Hospital; Herlev, Denmark

SNP, single nucleotide polymorphism

Key words: longevity, ageing, mortality, p53, Arg72Pro, SNP, polymorphism, cancer risk

ground allowing selection equilibriuTm to be established. These two assumptions, however, are not mSet when it comes to multifactorial diseases relevant to the ageing Ipopulation in modern affluent and fast D developing societies. Therefore, a priori it is quite possible that SNPs could be causative andT thus associated with multifactorial diseases, and even lifespan. the relative effect-size in most cases is probably small and in the order of 10–100% change of relative risk.

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 Arg72Pro substitution in the p53 protein has important influEence on cell death via increased apoptosis. Thus, the increased loIngevity C may be due to a generally increased robustness after a diagnosis of S any life-threatening disease. In contrast to widespread skepticism O on the importance of SNPs in humans, this gain-of-function p53 SNP of importance for cell repair has a profound influence on longevity.

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O Admittedly, the history of genetic association with common multifacDtorial diseases is full of irreproducible studies with a repro- duci bility ratio of 16%, probably due to inflated estimates in small . uEnder-powered case-studies, inadequate selection of controls, and bias favouring positive associations.4 These failures in the past imply that studies on genetic variations and their associa- tion with multifactorial diseases must be very large if the results are to be trusted, and they must include the relevant population suited to answer the questions asked with as little bias as possible. To meet these demands, large prospective studies of the general population is the gold-standard: in his proposal for a prospective study in the US, Francis Collins states that “…(genetic) associations and esti- mation of their magnitude, consistency and temporality (all key criteria for epidemiological evidence of causal relationships) are best obtained through prospective, population-based cohort studies”5 and that “…prospective cohort studies provide a valuable, feasible and, indeed, indispensable means of exploring the genetic basis of complex human diseases”.6 In Denmark such a prospective study, The Copenhagen City Heart Study, was already established in the

Introduction

After completion of the human genome project, more than ten N million single nucleotide polymorphisms (SNPs) have been identi- A fied;1-3 however, the importance of most SNPs for health and disease L is not understood. By definition, SNPs are genetic variations with an allele frequency abo8ve 1% in a given population. This definition 0 seemingly precludes that SNPs could have severe consequences for 0 survival of the individual; if carrying a given SNP was that disadvan- 2 tageous, it would soon disappear due to Darwinian selection. This argument has at least two implicit assumptions: (1) The SNP reduces fitness at an early still fertile age; (2) A constant environmental back-

The Copenhagen City Heart Study