Perspectives: The search for SNPs in the human genome is advancing; however, understanding the importance of such SNPs for mortality is limited. Inferring the impact on human health from knowledge of genetic variation to change of protein function further to influences 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 p73 and decreased location to mitochondria; at the cellular level, this protein change leads to decreased apoptosis and increased G cell cycle arrest, which we now demonstrate lead to increased survival after life-threatening diseases and overall survival of the entire person (Fig. 8). 

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

Figure 7. General population 5-year survival after a cancer diagnosis in p53 Arg72Pro Arg/Arg homozygotes, Arg/Pro heterozygotes, and Pro/Pro homozygotes. Only cancers diagnosed one year prior to blood sampling and afterwards were included. We followed participants with a cancer diagnosis from The Copenhagen City Heart Study. Reproduced with permission from Journal of Experimental Medicine, 2007; 204:1295-301.

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

The present study thus illustrates that large human studies are sine qua nons of modern biomedical research, and we believe that this represents another lesson from our study: laboratory and population-based research are each indispensable and complement each other in identifying and describing factors that contribute to human health and disease. In vitro, cell, and animal studies are extremely important for understanding basic mechanisms. However, results from such studies alone will never be able reliably to predict the effect in humans. To study such effects, studies in humans are necessary, preferably by using the golden standard of large population-based studies, as exemplified in the present study by the Copenhagen City Heart Study.

Function might improve clinical in intensive care, cardiology, neurology as well as in oncology patients. Expression profiles are now reaching clinical use; our work suggests that also germline genetic variations in the host organism influence prognosis. In our case, this single p53 polymorphism extends lifespan after a cancer diagnosis with several years. Interestingly, the improved prognosis in Arg/Pro heterozygotes and Pro/Pro homozygotes vs. Arg/Arg homozygotes seems to be relatively independent of the type of disease, indicating that the mechanism might be an unspecific improved robustness in the organism experiencing any life-threatening disease.

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