Arg72Pro polymorphism in TP53 is associated with all-cause mortality in type 2 diabetics



Rok publikování 2013
Druh Konferenční abstrakty
Popis Aims: The role of p53 protein in the prevention of tumor development through induction of cell cycle arrest or apoptosis is well established. However, p53 has also been shown to direct metabolic adaptations (namely regulation of glycolysis and, fatty acid oxidation) and subsequent cellular responses (such as antioxidant defence). Guanine to cytosine exchange in exon 4 (rs1042522) of the TP53 gene causes substitution of arginine to proline in the codon 72 leading to a slight reduction of protein activity associated with decreased apoptotic potential and therefore increased cancer risk. Recently, two large studies reported association of allele Arg72 with T2DM and there are also reports of its association with coronary artery disease. In this study we analysed the effect of TP53 SNP Arg72Pro on diabetes-related morbidity and mortality. Methods: Study comprised a total of 273 T2DMsubjects and 80 healthy subjects. Diabetics were prospectively followed for a median of 39 [IQR 21 - 59] months. Time-to-event analysis considered following end-points: [1] progression of diabetic kidney disease, [2] major cardiovascular event (i.e. non-fatal and fatal myocardial infarction or stroke, limb amputation) and [3] all-cause mortality. Genotyping for TP53 SNP Arg72Pro was performed by real time PCR. Results: Comparison of allele and genotype frequencies did not show significant difference between subjects defined based on baseline GFR and micro- and macroproteinuria stage or between diabetics and healthy subjects (P > 0.05, chi-square and Fisher-exact test). Cumulative incidence of renal disease progression was 22.3%, major cardiovascular event 18.7% and all-cause mortality 21.9%. Due to a low number of carriers of CC genotype, recessive model was tested only - the GG genotype was associated with faster rate of all-cause mortality compared to other genotypes (P=0.021, log-rank test). Discussion/Conclusion: Our results indicate that common genetic variation in TP53 may modulate the course and prognosis of T2DM subjects accelerating their mortality.
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