and disease is not. Therefore, skepti- cism among researchers of the value of SNP research is profound. We demonstrate that the p53 Arg72Pro SNP alone may prolong life on average 3 years, roughly equivalent to a quarter of the effect between smokers and non-smokers.8 Importantly, as smoking status is the strongest known common life-style predictor of death in the general population, o.ur study illus- E trates that the observed effect of T this p53 SNP is a very large one indeed.

Although Arg

Pro is a SNP I leadi

g to marked changes of the fu

ction of the guardian of the S genome p

, our study suggests I that this SNP is not associated with D risk of cancer or any other disease, maybe except for hematological malignancies. Instead, this SNP has a profound gene-dose dependent par- beneficial effect on

-year survival after a diagnosis of cancer, on since survival after other diseases, and on longevity. Thus, the increased longevity may be due to a general robustness after a diagnosis of any disease. This suggests that the Arg

Pro SNP is an important gain-of- genetic variant affecting the entire

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Figure 4. Morbidity (left) and overall mortality and mortality after disease (right) according to pN53 genotype in the general population.8 Participants were from the Copenhagen City Heart Study. Numbers of ticipants vary slightly because some participants were excluded due to development of prior to The sum of deaths in the disease groups do not add up to give the numbers of events in overall mortality many participants had more than one disease.

increased robustness after a diagnosis of any life-threatening disease. This suggests that the p53 Arg72Pro SNP is an important gain-of- function genetic variant affecting the entire person.

C N E I C S O I B S E

The reduced mortality in Arg/Pro hetero- zygotes and Pro/Pro homozygotes vs. Arg/Arg homozygotes, which could result from a gener- ally increased robustness caused by decreased pro-apoptotic activity and increased cell cycling arresting abilities of the Pro72 vs. the Arg72 version of p53,29,33,41 thereby protecting a person experiencing any critical illness. Our study is incapable of dissecting which one of the two main functional changes in the Pro72 version that causes these benefi- cial effects. Inhibition or eradication of p53 function protects ischemic cells from apop-

L Figure 5. General population 12-year survival (left) and longevity (right) in p53 Arg72Pro homozygotes, Arg/Pro het erozygotes and Pro/Pro homozygotes. We followed 9,219 from the Copenhagen City Heart Study. Reproduced with permission from Journal of Medicine, 2007; 204:1295-301.8 Copyright 2007 Rockefeller University Press.

tosis in the liver, heart and brain.42-44 In coronary patients, the Pro72 allele was associated with stepwise increase of minimal lumen diameter in the coronary arteries after stent implantation, indicating a beneficial effect of the modulation of the function of p53 by the Arg72 to Pro72 substitution.45 Likewise, in patients with traumatic brain injury, Arg/Arg homozygotes vs. Arg/Pro heterozygotes and Pro/Pro homozygotes combined had a 3-fold increased risk of adverse outcome at the time of discharge from hospital, probably due to larger ischemic borderzones around the cerebral lesions in the acute phase.23 We therefore speculate that modulation of p53

insignificantly stepwise reduced with increasing number of Pro72 © alleles (trend-test, p = 0.13) (Fig. 4, right). For all analyses described above, multifactorial adjustment for other potential confounders (cumulative tobacco consumption, smoking status, body mass index, alcohol consumption, plasma cholesterol, systolic blood pressure and physical inactivity) gave similar risk estimates (data not shown).

Perspectives

The search for SNPs in the human genome is advancing however, understanding of the importance of such SNPs for

. E T U B I R T S I

 Mortality, % © p53 Pro72 allele frequency, % @80 2960: 2840 2720: 260 2560 70 80 90Age, years 

Figure 6. Frequency of mortality (black dots) and the p53 Arg72Pro Pro allele (green dots) as a function of age in five-year groups.8 Participants were from the Copenhagen City Heart Study.

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oSoNap53 Arg72Pro— Arg/Arg— Arg/Pro— Pro/ProNa1x2D£2g® 50)c2©3©a0:0 1 2 3 4 5Time after cancer diagnosis, years 

Figure 8. Effect of the p53 Arg72Pro polymorphism at the level of protein sequen ce, protein function, cell and whole organism.

insight is limited. Inferring impact on human health from knowledge of genetic variation to change of protein function further to influ- . E ences on the cellular level and finally to affect the entire person can be extremely difficult: the DNA G251C substitution in the TP53 gene causing the Arg72Pro substitution of p53 leads to decreased binding to p7328 and decreased location to mitochondria;29 at the cellular level this protein change leads to decreased apoptosis29 and increased G cell cycle arrest,41 which we now demonstrate lead to 1 increased survival after life-threatening diseases and overall survival of the entire person (Fig. 8).

Figure 7. General population 5-year survival after a cancerS diagnosis in p53 Arg72Pro Arg/Arg homozygotes, Arg/Pro heterozygoOtes and Pro/Pro homozygotes. Only cancers diagnosed one year prior to blood sampling I and afterwards were included. We followed participants with a cancer diagnosis from The Copenhagen City Heart Study. Reproduced with permission from Journal of Experimental e, 2007; 204:1295-301.8