TP53 Arg72Pro, mortality after cancer, and all-cause mortality in 105,200 individuals

Jakob B Kodal,Signe Vedel-Krogh,Stig E Bojesen,Børge G Nordestgaard,Camilla J Kobylecki

doi:10.1038/s41598-017-00427-x

Jakob B Kodal, Signe Vedel-Krogh + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-00427-x

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Abstract

Rs1042522 (Arg72Pro) is a functional polymorphism of TP53. Pro72 has been associated with lower all-cause mortality and lower mortality after cancer. We hypothesized that TP53 Pro72 is associated with lower mortality after cancer, lower all-cause mortality, and with increased cancer incidence in the general population in a contemporary cohort. We genotyped 105,200 individuals aged 20–100 years from the Copenhagen General Population Study, recruited in 2003–2013, and followed them in Danish health registries. During follow-up 5,531 individuals died and 5,849 developed cancer. Hazard ratios for mortality after cancer were 1.03 (95% confidence interval:0.93–1.15) for Arg/Pro and 0.96 (95% CI:0.79–1.18) for Pro/Pro versus Arg/Arg. Hazard ratios for all-cause mortality were 0.99 (95% CI:0.93–1.04) for Arg/Pro and 1.09 (95% CI:0.98–1.21) for Pro/Pro versus Arg/Arg. Risk of cancer specific mortality, cardiovascular mortality, and respiratory mortality were not associated with Arg72Pro genotype overall; however, in exploratory subgroup analyses, genotype-associated risks of malignant melanoma and diabetes were altered. Considering multiple comparisons the latter findings may represent play of chance. The TP53 Arg72Pro genotype was not associated with mortality after cancer, all-cause mortality, or cancer incidence in the general population in a contemporary cohort. Our main conclusion is therefore a lack of reproducing an effect of TP53 Arg72Pro genotype on mortality.

Highlights

The germline single nucleotide polymorphism rs1042522 (Arg72Pro) is an arginine (Arg) to proline (Pro) substitution in codon 72, and the two p53 variants differ in how they influence downstream cellular processes; the Arg[72] variant induces apoptosis five times better than the Pro[72] variant, likely through a greater ability of the Arg[72] variant to localize to the mitochondria[6] and to increase transcription of a number of pro-apoptotic p53-regulated genes[7]
The Arg72Pro polymorphism has been extensively studied as a risk factor for development of cancer in candidate gene studies[8,9,10,11,12,13]; candidate gene studies can be of low quality and may suffer from a variety of reporting, analysis, and genotyping biases[14,15,16]
Fewer studies have examined the association of the Arg72Pro polymorphism with all-cause mortality

Summary

Introduction

The germline single nucleotide polymorphism rs1042522 (Arg72Pro) is an arginine (Arg) to proline (Pro) substitution in codon 72, and the two p53 variants differ in how they influence downstream cellular processes; the Arg[72] variant induces apoptosis five times better than the Pro[72] variant, likely through a greater ability of the Arg[72] variant to localize to the mitochondria[6] and to increase transcription of a number of pro-apoptotic p53-regulated genes[7]. We used Cox proportional hazards regression analysis adjusted for sex and age (as time scale), with entry at birth or at the start of the Danish cancer registry if individuals were born before January 1, 1943.

Results

Conclusion