Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time

Reiling, Erwin; Lyssenko, Valeriya; Boer, Jolanda M. A.; Imholz, Sandra; Isomaa, Bo; Tuomi, Tiinamaija; Groop, Leif; Dollé, Martijn E.T.

doi:10.1038/ejhg.2011.240

Cited by 26 publications

(31 citation statements)

References 27 publications

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“…In keeping with the latter, Burgdorf and coworkers’ metaanalysis of diabetes did find the R72 allele to increase risk of Type 2 diabetes by 6% [39], though there are no data for diabetic nephropathy per se . A relationship with BP, has also been reported [40], but we do not confirm this. There are large differences in frequency between continental populations, with the ancestral P72 allele common in Africa, and the R72 allele common in European and Asian populations (Table 5).…”

Section: Discussioncontrasting

confidence: 89%

Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in ACE and TP53

et al. 2016

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BackgroundAboriginal Australians are at high risk of cardiovascular, metabolic and renal diseases, resulting in a marked reduction in life expectancy when compared to the rest of the Australian population. This is partly due to recognized environmental and lifestyle risk factors, but a contribution of genetic susceptibility is also likely.MethodsUsing results from a comprehensive survey of one community (N = 1350 examined individuals), we have tested for familial aggregation of plasma glucose, arterial blood pressure, albuminuria (measured as urinary albumin to creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR), and quantified the contribution of variation at four candidate genes (ACE; TP53; ENOS3; MTHFR).ResultsIn the subsample of 357 individuals with complete genotype and phenotype data we showed that both UACR (h2 = 64%) and blood pressure (sBP h2 = 29%, dBP, h2 = 11%) were significantly heritable. The ACE insertion-deletion (P = 0.0009) and TP53 codon72 polymorphisms (P = 0.003) together contributed approximately 15% of the total heritability of UACR, with an effect of ACE genotype on BP also clearly evident.ConclusionsWhile the effects of the ACE insertion-deletion on risk of renal disease (especially in the setting of diabetes) are well recognized, this is only the second study to implicate p53 genotype as a risk factor for albuminuria - the other being an earlier study we performed in a different Aboriginal community (McDonald et al., J Am Soc Nephrol 13: 677-83, 2002). We conclude that there are significant genetic contributions to the high prevalence of chronic diseases observed in this population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0396-2) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 89%

Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in ACE and TP53

et al. 2016

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“…These data suggest that the R72 variant may predispose individuals to obesity, which subsequently leads to increased susceptibility to type 2 diabetes. In support of this hypothesis, a recent cohort study of over 2,500 Dutch and Finnish subjects found a significant association between R72 and increased waist circumference (Reiling et al, 2012). Similarly, a separate study showed that the association between BMI (body mass index) and diabetes is much stronger in homozygous R72 individuals (Gloria-Bottini et al, 2011).…”

Section: Discussionmentioning

confidence: 88%

The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction

et al. 2016

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SUMMARY p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism and inflammation.

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“…A cohort study of over 2,500 Dutch and Finnish subjects found that the R72 variant is associated with increased waist circumference (Reiling, et al 2012). These data suggested that the R72 variant might predispose individuals to adiposity/obesity, and that this might then lead to increased risk for the development of type 2 diabetes.…”

Section: Polymorphisms In the P53 Pathway: The Codon 72 Polymorphism mentioning

confidence: 99%

The role of the p53 tumor suppressor in metabolism and diabetes

Kung

Murphy

2016

Journal of Endocrinology

135

104

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In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53’s role in metabolism may also be consequential to tumor suppression. Here we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis, and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic.

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Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time

Cited by 26 publications

References 27 publications

Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in ACE and TP53

Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in ACE and TP53

The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction

The role of the p53 tumor suppressor in metabolism and diabetes

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