The Copenhagen City Heart Study

In this study, participants aged 20 to 95 years were recruited at random from the Danish general population in Copenhagen.7,8 Participants have been interviewed and examined at three occasions in 1976–78, 1981–83 and 1991–94, supplementing the cohort with new participants at the second and third occasion. At each examina- tion, participants were interviewed and examined, and in 1991–94 DNA was isolated from >9000 participants.

*Correspondence to: Stig E. Bojesen; Department of Clinical Biochemistry; Herlev Hospital; Copenhagen University Hospital; Herlev Ringvej 75; Herlev DK-2730 Denmark; Tel.: +45.4488.3843, Fax: +45.4488.3311; Email: stebo@heh.regionh.dk

The national Danish health registries are virtually 100% complete collecting health data on all Danish citizens. This globally unique feature allows for comprehensive analyses of mortality and all

Submitted: 10/30/07; Accepted: 11/01/07

Previously published online as a Cell Cycle E-publication:

end-points leading to hospitalization. Therefore, Danish population- based studies are especially suited to answer questions regarding the total health effect of genetic variants.

  Ch nnn GB.Cell cycle DNA repair Apoptosisarrestp53 Arg72 Ttp53 Pro72 t t 

The advantages of The Copenhagen City Heart Study thus are its size, the random selection of participants from the general population, the long follow-up, the thorough phenotyping and the completeness of the national Danish health registries. The homog- enous Danish population precludes the need for ethnic stratification, and makes The Copenhagen City Heart Study more powerful for genetic studies than most cohorts from admixed populations. These characteristics make The Copenhagen City Heart Study a unique resource for studying effects of genetic variations.

Figure 1. Functional differences between the Arg72 and Pro72 versions of p53.

p53

the two forms of the p53-protein.19,28-35 In short, the Arg72 form U is more efficient in apoptosis induction, whereas the Pro72 form B induces more G arrest and is better at activating p53 dependent 1 I DNA repair (Fig. 1). The frequency ofR the Pro72 allele of Arg72Pro ranges from 70% among South ATfricans to 23% among Western Europeans (Fig. 2).22 Pro72 is pS robably the ancient allele, but the I reason for the high frequency of Arg72 among Europeans is unclear. D The gradient from Europe to Africa according to latitude suggests that the Pro72-allele a better protector against sunlight induced diseases;36 however, the few epidemiological studies examining the Arg72Pro and risk of skin cancer disagree.37,38

p53 [OMIM # 191170] is a tumor suppressor and its 19 kb gene (TP53) is situated on chromosome 17p13.1. It consists of 11 exons resulting in a transcript of 2,629 bp and a protein of 393 amino acids. In half of all human cancers, the tumor suppressor p53 is damaged by somatic mutation in tumor cells.9 This protein is at the centre of cell regulatory pathways, influencing transcription and activity of several replication and transcription factors, and is known as the guardian of the genome. In case of UV-radiation, proto- oncogene activation or DNA damage, p53 is activated. p53 acts through several pathways when reacting to cellular stress. Apoptosis, cell cycle arrest at the G checkpoint, and cellular senescence are all 1 mechanisms triggered by activated p53,10 thereby preventing cancer growth. When p53 is damaged, cancer cells continue to multiply. In agreement with this, transgenic mice overexpressing p53 are virtually immune to the development of tumors.11

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Due to th e central role of p53 in the development of cancer, and O the demonstrated functional differences between the Arg72 and D the Pro72 allele, it has been hypothesized that this polymorphism is as sociated with risk of cancer. Using mainly case-control studies, . alEmost all neoplastic disease subtypes have been associated with the Arg72Pro polymorphism, but with conflicting results.22,24,27 Much research has concentrated on the risk of cervical cancer, but a recent meta-analysis concluded that the aggregated change of risk across the three genotypes was “essentially null”.22 Risk of breast cancer has also been examined in several studies with conflicting results, but the largest case-control study comprising 8743 cases and 10,618 controls produced risk estimates for both Arg/Pro heterozygotes and Pro/Pro homozygotes of 1.0 (95 % confidence interval, 0.9–1.1) vs. Arg/Arg homozygotes.39

Despite these beneficial effects of increased p53 activity for cancer resistance, mice overexpressing p53 age prematurely and E even die earlier than their wild-type counterparts.11 Thus, activa- I tion of p53 is beneficial when the organism is young, butC in older organisms it might reduce lifespan and even augment cSancer risk,12 so-called antagonistic pleiotropy.10,13 In accordaOnce with this concept, p53 accelerates aging when responding Ito cellular stress.14 B In cell cultures, inactivation of normal p53 activity in senescent cells completely reverses the senescent h arrest, and allows the cells to resume cell divisions for many despite critically shortened telomeres.15

Arg72Pro and Morbidity

Germline truncating mutationNs of TP53, the gene coding for p53, are associated with a rar Ae autosomal dominant disorder, the Li-Fraumeni syndrome.16 T Lhis syndrome is chacterized by multiple primary neoplasms in ch ildren and young adults, with a predomi- nance of soft-tissue sarcomas, osteosarcomas, breast cancer, brain