Pro Allele Research Articles

Interaction Effects of the Leu162Val PPARαand Pro12Ala PPARγ2 Gene Variants with Renal Function in Metabolic Syndrome Population

Leu162Val PPARα and Pro12Ala PPARγ2 were investigated for their individual and their interactive impact on MS and renal functionality (RF). 522 subjects were investigated for biochemical and anthropometric measurements. The diagnosis of MS was based on the IDF definition (2009). The HOMA 2 was used to determine HOMA-β, HOMA-S and HOMA-IR from FPG and FPI concentrations. RF was assessed by estimating the GFR. PCR-RFLP was performed for DNA genotyping. Allele frequencies were 0.845 for Pro and 0.155 for Ala, and were 0.915 for Leu and 0.085 for Val. We showed that carriers of the PPARα Val 162 allele had lower urea, UA and higher GFR compared to those homozygous for the Leu162 allele. Subjects carried by PPARγ2Ala allele had similar results. They also had reduced FPG, FPI and HOMA-IR, and elevated HOMA-β and HOMA-S compared to those homozygous for the Pro allele. Subjects were divided into 4 groups according to the combinations of genetic alleles of the 2 polymorphisms. Subjects carrying the Leu/Val with an Ala allele had lower FPG, PPI, HOMA-IR, urea, UA levels, higher HOMA-β, HOMA-S and GFR than different genotype combinations. Leu162Val PPARα and Pro12Ala PPARγ2 can interact with each other to modulate glucose and insulin homeostasis and expand their association with overall better RF.

Association between BRIP1 (BACH1) polymorphisms and breast cancer risk: a meta-analysis

Inconsistency of reported associations between the Pro919Ser polymorphism in the BRCA1 interacting protein 1 (BRIP1) gene and breast cancer prompted us to undertake a meta-analysis. Although investigated by fewer studies, we have also studied the risk associated with the two additional BRIP1 polymorphisms, C47G and G64A, and breast cancer riskWe conducted searches of the published literature in MEDLINE through PubMed up to October 2012. Individual data on 5,122 cases and 5,735 controls from eight published case-control studies were evaluated for the Pro919Ser polymorphism. Accordingly, C47G and G64A polymorphisms were studied in 1,539 cases and 1,183 controls, and 667 and 782, respectively.In the overall analysis, association was lacking between the Pro919Ser polymorphism and breast cancer risk (odds ratio [OR] 0.98-1.02), materially unchanged when confined to subjects of European ancestry (OR 0.96-1.03) or even in the high-powered studies (OR 0.97-1.03). In the menopausal subgroups, premenopausal women followed the null pattern (OR 0.94-0.98) for the Pro and Ser allele contrasts, but not for the Pro-Ser genotype comparison where significant increased risk was observed (OR 1.39, P = 0.002). The postmenopausal women (>50 years) exhibited a range of pooled effects from protection (OR 0.83, P = 0.11) in the Pro-Ser genotype to slightly increased risk (OR 1.12-1.16, P = 0.28-0.42) in the Pro and Ser allele comparisons. The G64A polymorphism effects were essentially null (OR 0.90-0.98), but C47G was found to confer non-significantly increased risk under all genetic models (OR 1.27-1.40).Upon conclusion, overall summary estimates imply no associations but suggest susceptibility among carriers of the C47G polymorphism and Pro-Ser genotype in premenopausal women. The premenopausal findings and variable outcomes in postmenopausal women require more studies for confirmation.

Association of common WRAP 53 variant with ovarian cancer risk in the Polish population

Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogensis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53–TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53–WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53.

Amerindians show no association of PPAR-γ2 gene Ala12 allele and obesity: an “unthrifty” variant population genetics

Obesity is for many scholars the most important starting status that gives rise to Metabolic Syndrome (MS) and Type 2 Diabetes (T2D). In the present paper, a genetically homogeneous Amerindian population, as defined by HLA genes, has been genotyped for one of the MS and T2D predisposing genes: PPAR-γ Ala12 and Pro 12 variants. Ala12 has been negatively associated with obesity, but other authors do not find such an association. Notwithstanding, a meta-analysis that used many subjects clearly demonstrated that PPAR-γ Ala12 bearing ones had a reduced risk for T2D. Our results show that Amerindians do not have association of PPAR-γ2 Ala12 and obesity; the latter was measured by waist circumference values after taken specific Amerindian normal waist parameters. Also, a population genetics study indicates that Pro12 allele was the wild allele, which must have occurred before modern humans left Africa. Ala12 may have appeared in Caucasoids later on, according to our comparisons. Negroids tend to show low or null Ala 12 allele frequencies, while most other populations have a significant frequency, particularly European Caucasoids. This may suggest that appearance of Ala12 allele occurred after populations adapted to an agricultural feeding.

Association between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population

Genetic polymorphisms of p53 codon 72 are thought to have significant effects on the metabolism of environmental carcinogens and thus on lung cancer risk, but the reported results are not always consistent. The aim of this study is to investigate the relationship between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population. A population-based control study was conducted in 360 lung cancer patients and 360 cancer-free controls. The genotype of the p53 codon 72 was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Patients with lung cancer had a significantly lower frequency of Pro/Pro genotype [odds ratio (OR) = 0.58, 95 % confidence interval (CI) = 0.40, 0.84; P = 0.004] and Pro allele (OR = 0.72, 95 % CI = 0.59, 0.89; P = 0.002) than controls. Patients with squamous cell carcinoma had also a significantly lower frequency of Pro/Pro genotype (OR = 0.45, 95 % CI = 0.25, 0.82; P = 0.009). In the analysis combining p53 codon 72 polymorphisms and smoking, smokers who had smoked for more than 30 pack-years had a significantly lower frequency of Pro/Pro genotype (OR = 0.52, 95 % CI = 0.30, 0.92; P = 0.03) compared with non-smokers. This study suggests that p53 codon 72 polymorphisms play a role in the development of lung cancer and modifies the risk for smoking-related lung cancer in a Chinese population.

The Pro Allele of the p53 Codon 72 Polymorphism Is Associated with Decreased Intratumoral Expression of BAX and p21, and Increased Breast Cancer Risk

BackgroundThe TP53 Arg72Pro polymorphism encodes two p53 variants with different biochemical properties. Here we investigated the impact of this polymorphism on the expression of key p53 target genes in a panel of human breast carcinomas, breast cancer risk, and age at onset.Methodology/Principal FindingsThe Arg72Pro polymorphism was genotyped in 270 breast cancer patients and 221 control subjects. In addition, the Arg72Pro genotype of 116 breast tumors was determined, and correlated with intratumoral mRNA expression of TP53 and its key target genes MDM2, p21, BAX, and PERP, as quantified by qRT-PCR. We found a significantly increased breast cancer risk associated with the Pro-allele (per-allele odds ratio, 1.46; 95% confidence interval, 1.08–1.99), and a significantly later mean age at breast cancer onset for Pro/Pro patients (63.2±18 years) compared to Arg/Arg patients (58.2±15 years). The frequency of somatic TP53 inactivation was 25.4% in Arg/Arg, 20.9% in Arg/Pro, and 16.7% in Pro/Pro patients, which may reflect a higher selective pressure to mutate the Arg-allele. The median mRNA levels of p21 and BAX in the tumors of Pro-allele carriers were significantly reduced to 55.7% and 76.9% compared to Arg/Arg patients, whereas p53, MDM2 and PERP expression were hardly altered.Conclusions/SignificanceThe p5372Arg variant appears to be a more potent in vivo transcription factor and tumor suppressor in human breast cancer than the p5372Pro variant. The Arg72Pro genotype has no significant effects in patients with TP53 mutated tumors, in which p53 is non-functional.

The p53 Codon 72 PRO/PRO Genotype May Be Associated with Initial Central Visual Field Defects in Caucasians with Primary Open Angle Glaucoma

BackgroundLoss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field.MethodsGenotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry.ResultsThe p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p = 2.7×10−5). We replicated this finding in the GIST cohort (p = 7.3×10−3, and in the pooled sample (p = 6.6×10−7) and in a meta-analysis of both the US and GIST datasets (1.3×10−6, OR 2.17 (1.58–2.98 for the PRO allele).ConclusionsThese results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.

1122P - Inherited Abnormalities in Genes That During the Apoptosis Process and Cutaneous Melanoma Risk

ABSTRACT Background P53 (guardian of the genome), MDM2 (p53 inhibitor), BCL2 (anti-apoptotic) and BAX (proapoptotic) genes remove cells damaged by ultraviolet (UV) rays of sunlight and, therefore, are related to the origin of cutaneous melanoma (CM). All these genes are polymorphic in humans. The Arg wild allele of the P53 Arg72Pro polymorphism is more efficient than the variant Pro allele at inducing apoptosis. The variant G and A alleles of MDM2 T309G and the BCL2 C (-948) A polymorphisms, and the variant A allele of the BAX G(-248)A polymorphism are related to higher and lower expressions of the encoded proteins, respectively, than their wild T, C and G alleles. This study aimed to clarify the roles of the above-mentioned genetic polymorphisms in the risk and clinical manifestation of the tumor. Material and methods In this case-control study, genomic DNA from peripheral blood of 150 consecutive CM patients (75 males and 75 females, 138 Caucasians and 12 non-Caucasians aged 20-89 years) and 150 healthy subjects, matched by age, gender and race, was analyzed by polymerase chain reaction followed by enzymatic digestion. Results The frequencies of the P53 ArgArg and the BCL2 AA genotypes were higher in patients than in controls (58.7% versus 44.7%, P= 0.01) and (28.0% versus 15.3%, P= 0.004), respectively. Carriers of these genotypes had a 1.86 and 2.87-fold increased risk for CM than those with the remaining genotypes, respectively. Excesses of the P53 ArgArg plus BCL2 AA and P53 ArgArg plus BAX AA were seen in patients when compared to controls (36.1% versus 16.9%, P= 0.002) and (29.5% versus 15.3%, P= 0.008). Carriers of these genotypes had a 3.43 and 2.71-fold increased risk for CM than others, respectively. Conclusions The data suggest that P53 Arg72Pro, BCL2 C(-248)A and BAX G(-248)A polymorphisms, alone or combined, alter the risk for CM in our region. We believe that carriers of specific genotypes of the above-mentioned genes should receive additional recommendation to avoid exposition to sunlight, in addition to frequently being evaluated by a dermatologist for early disease diagnosis. Financial support: (FAPESP) Disclosure All authors have declared no conflicts of interest.

Ala/AlaGenotype ofPro12AlaPolymorphism in thePeroxisome Proliferator-Activated Receptor-γ2Gene Is Associated with Obesity and Insulin Resistance in Asian Indians

We determined the association of the Pro12Ala polymorphism of the peroxisome proliferator activated receptor (PPAR)-γ2 gene with obesity, insulin resistance (IR), and lipids in Asian Indians without diabetes in north India. In this cross-sectional study (n = 495; 279 males and 216 females, 18-60 years of age), anthropometric (body mass index, waist and hip circumferences, and skinfold thickness) and biochemical (fasting glucose, lipid profile, fasting insulin, leptin, and adiponectin) parameters were assessed. Polymerase chain reaction-restriction fragment length polymorphism analysis was used for identification of individual genotypes. Frequencies of the Pro and Ala alleles were 0.89 and 0.11, respectively. The genotype frequencies (%) of Pro/Pro, Pro/Ala, and Ala/Ala were 82.6, 14.7, and 2.7, respectively, without any gender differences. The frequency of the Ala/Ala genotype was higher in obese than in nonobese subjects (4.9% vs. 1.5%, P = 0.06). The Ala/Ala genotype was associated with higher values of hip circumference, subscapular skinfold thickness, and sum of four skinfold thickness than the Pro/Pro and Pro/Ala genotypes (P<0.05). Using a multivariate logistic regression model after adjusting for age, sex, and insulin, subjects with the Ala/Ala genotype showed a high risk of obesity (odds ratio [OR], 3.2, 95% confidence interval [CI] 1.2-12.9) and IR (OR, 3.6, 95% CI: 1.04-12.4). The Ala/Ala genotype of the PPAR-γ2 gene is associated with obesity and IR in Asian Indians without diabetes living in north India.

Updated Meta-analysis of the TP53 Arg72Pro Polymorphism and Gastric Cancer Risk

The p53 tumor suppressor pathway plays an important role in gastric cancer (GC) development. Auto-regulatory feedback control of p53 expression is critical to maintaining proper tumor suppressor function. So far, several studies between p53 Arg72Pro polymorphism and GC have generated controversial and inconclusive results. To better assess the purported relationship, we performed a meta-analysis of 19 publications. Eligible studies were identified by searching the Pubmed database. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess any link. Overall, a significant association was detected between the p53 Arg72Pro polymorphism and GC risk (Pro-allele vs. Arg-allele: OR=1.05, 95%CI=1.01-1.08; Pro/Pro vs. Arg/Arg: OR=1.13, 95%CI=1.04-1.22). Moreover, on stratified analysis by race, significantly increased risk was found for Asian populations (Pro-allele vs. Arg-allele: OR=1.06, 95%CI=1.02-1.10; Pro/Pro vs. Arg/Arg: OR=1.16, 95%CI=1.07-1.26; Pro/Pro+Pro/Arg vs. Arg/Arg: OR=1.58, 95%CI=1.09-2.27). Our study provided evidence that the p53 72Pro allele may increase GC risk in Asians. Future studies with larger sample size are warranted to further confirm this association in more detail.

How Contemporary Human Reproductive Behaviors Influence the Role of Fertility-Related Genes: The Example of the P53 Gene

Studies on human fertility genes have identified numerous risk/protective alleles involved in the occurrence of reproductive system diseases causing infertility or subfertility. Investigations we carried out in populations at natural fertility seem to suggest that the clinical relevance that some fertility genes are now acquiring depends on their interaction with contemporary reproductive behaviors (birth control, delayed childbearing, and spacing birth order, among others). In recent years, a new physiological role in human fertility regulation has emerged for the tumor- suppressor p53 gene (P53), and the P53 Arg72Pro polymorphism has been associated with recurrent implantation failure in humans. To lend support to our previous observations, we examined the impact of Arg72Pro polymorphism on fertility in two samples of Italian women not selected for impaired fertility but collected from populations with different (premodern and modern) reproductive behaviors. Among the women at near-natural fertility (n = 98), the P53 genotypes were not associated with different reproductive efficiency, whereas among those with modern reproductive behaviors (n = 68), the P53 genotypes were associated with different mean numbers of children [Pro/Pro = 0.75<Pro/Arg = 1.7<Arg/Arg = 2, (p = 0.056)] and a significant negative relationship between the number of children and P53 Pro allele frequencies (p = 0.028) was observed. These results are consistent with those of clinical studies reporting an association between the P53 Pro allele and recurrent implantation failure. By combining these findings with previous ones, we suggest here that some common variants of fertility genes may have become “detrimental” following exposure to modern reproductive patterns and might therefore be associated with reduced reproductive success. Set within an evolutionary framework, this change could lead to the selection of a set of gene variants fitter to current reproductive behaviors as the shift to later child-bearing age in developed countries.

Abstract 1183: Monoallelic expression in codon 72 of TP53 in heterozygote individuals

Abstract Background &amp; Aim: Correlations between DNA variation and human phenotypic differences, such as susceptibility to certain diseases, are not well understood. Polymorphisms can contribute to the observed variation in complex human traits, but their relative contributions remain to be determined. Expression differences between alleles of the same gene have been observed, contributing to phenotypic variation between individuals. Studies showed that variations exist in the relative allelic expression levels in certain genes of heterozygote individuals. Polymorphism at codon 72 of TP53 results in either Arginine or Proline, whose functional significance in carcinogenesis is controversial. Studies showed that the Pro72 is less efficient than Arg72 allele in suppressing cell transformation and inducing apoptosis. We have investigated if the expression of these p53 polymorphs is selectively regulated, using mRNA and DNA from colorectal cancer (CRC). Methods: 89 non-related patients treated at ACCamargo Hospital/Brazil were evaluated. DNA/RNA were isolated from frozen tumor tissue using phenol/chloroform protocol and evaluated by sequencing. Associations were analyzed by Pearson Chi-Square or Fisher Exact tests and Multiple Logistic Regression. Results: We found 24 (27%) heterozygotes tumors and 10 (41.7%) of these showed monoallelic expression: 70% (7/10) of them preferentially expressed the Pro allele. Thus, the allele frequencies showed a discrete decrease, from 0.26 for Pro allele of expression analysis to 0.25 for Pro allele of tumor genomic analysis. Previous results revealed that the p53 codon 72 expression was significantly associated with gender (P= .037), recurrence (P= .005), dirty tumor necrosis (P= .025), border pattern of tumor growth (P= .05), post chemoradiotherapy use (P= .002), p53 immunohistochemistry expression (P= .041) and TP53 mutation (P= .004), suggesting that the presence of at least one Arg72 allele is associated with better prognosis. According to multiple logistic regression the variable independently associated with the presence of the Arginine allele is the absence of tumor necrosis factor (OD= 8.64/P= .047). This is the first report describing the monoallelic expression of the p53 codon 72 in CRC and revealed that heterozygotes preferentially express the Pro allele, suggesting that the Pro allele is selectively activated during CRC development. Conclusions: The expression of the different p53 polymorphs is selectively regulated in Pro72Arg heterozygotes individuals. The silent Arg allele seems to have a negative relation with cancer susceptibility, since it is better in inducing apoptosis. The differences in the expression of heterozygotes resulted in an increase in the total numbers of Pro expressers in this cancer population. Thus, the expression status of the p53 polymorphs, rather than the genotypic status, might be a useful indicator for cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1183. doi:1538-7445.AM2012-1183

Abstract 727: Homozygosity for Arg of p53 codon 72 correlates with poor prognosis in Puerto Rican patients with head and neck squamous cell carcinoma

Abstract Objective: Genetic variations at codon 72 of p53 gene results in altered activities for p53 and are suggested as a potential cancer risk. However, epidemiologic findings have been inconsistent. The p53 gene has a polymorphic site at exon 4 codon 72, which, in an occurrence of a base substitution, can produce Proline or Arginine (Arg72Pro). This polymorphism is differentially dispersed among different ethnic populations. The objective of this study is to evaluate the association between p53 polymorphism and head and neck squamous cell carcinoma (HNSCC) in the Puerto Rican population. Methods: Genotyping of the p53 polymorphism at exon 4 codon 72 was performed using PCR-based restriction fragment polymorphism (PCR-RFLP) in a study with 72 HNSCC patients. Correlations between clinicopathological parameters and p53 polymorphism were analyzed by Fisher's exact test and chi-square when suitable. Survival analysis of HNSCC patients, with each type of p53 genotype, was performed using Mantel-Cox test. Results: The frequencies for homozygote Arg allele were 34.7% in HNSCC cases and 31.1% in controls. The Pro allele carriers (Arg/Pro or Pro/Pro) had a frequency of 65.3% in HNSCC cases and 68.9% in healthy controls. The OR of HNSCC cancer-associated with the Arg-Arg genotypes of codon 72 was 1.18 [95% confidence interval (CI): 0.53-2.61]. Survival analysis showed that HNSCC patients with the Arg/Arg allele had a poorer survival rate compared to patients with the Pro allele (Hazard Ratio = 2.40, 95% CI: 1.27-4.56, P=0.0074). Also, there were differences in survival based on patient's genotype and response to treatment. However, no statistically significant association was found between p53 polymorphic variants and gender, age, risk factors and staging. Conclusion: Our results suggest that homozygosity for Arg of p53 Arg72Pro may have a role in the progression of HNSCC in the Puerto Rican population. Detection of the p53 polymorphic variants may be used as an indicator of prognosis in HNSCC patients. Accurate prognosis in HNSCC will help clinicians to establish proper treatment and increase the survival of HNSCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 727. doi:1538-7445.AM2012-727

P53 codon 72 polymorphism and endometriosis: a meta-analysis

p53 tumour suppressor gene Arg72Pro polymorphism has been associated with endometriosis. However, the current available data were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and endometriosis. Electronic screening of PubMed library was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. Six published studies, including 749 endometriosis and 857 controls were identified. The overall results suggested that the variant genotypes were not associated with the endometriosis risk (Pro/Pro + Arg/Pro vs. Arg/Arg: OR = 1.552, 95% CI 0.916-2.632, p = 0.103). In the stratified analysis, individuals carried the Pro allele in a dominant model had increased risk of endometriosis (OR = 2.595, 95% CI 1.005-6.702, p = 0.049) in Asian subjects. The symmetric funnel plot, the Egger's test (p = 0.602), and the Begg's test (p = 0.167) were all suggestive of the lack of publication bias. However, the association was not significant between this polymorphism and endometriosis in Caucasian (OR = 1.005, 95% CI 0.755-1.337, p = 0.972). This meta-analysis suggests that p53 codon 72 Pro/Pro + Arg/Pro genotypes are associated with increased risk of endometriosis in Asian. To validate the association between p53 codon 72 polymorphism and endometriosis, further studies with larger participants worldwide are needed.

P53 codon 72 polymorphism and coronary artery disease: Evidence of interaction with ACP1

SummaryBackgroundCommon biological features between cancer and atherosclerosis suggest possible association of p53 with atherosclerotic diseases, but data on such a relationship are controversial, suggesting interactions with other variables. Acid phosphatase locus 1 (ACP1) is a polymorphic gene that controls the synthesis of an enzyme involved in important metabolic functions. Since ACP1 is associated with coronary artery disease (CAD), we searched for possible interactions between this enzyme and p53 codon 72 polymorphism with regard to their effects on susceptibility to CAD.Material/MethodsThe study included 381 patients admitted to the hospital for cardiovascular disease (232 patients with CAD and 149 with other cardiovascular problems) and 97 healthy newborns.ResultsThe proportion of subjects carrying the *Pro allele of p53 codon 72 and the high activity *B*C genotype of ACP1 is higher in CAD (10.3%) than in non-CAD patients (2.0%) and in healthy newborns (6.2%).ConclusionsThe data suggest an interaction between p53 codon 72 and ACP1 wherein a positive effect of the p53 *Pro allele on susceptibility to CAD occurs, but only in the presence of the ACP1 genotype characterized by high enzymatic activity.

Meta-analysis demonstrates association between Arg72Pro polymorphism in the P53 gene and susceptibility to keloids in the Chinese population

Although there is evidence suggesting genetic susceptibility for keloids, studies investigating the association between Arg72Pro polymorphism in the P53 gene and tendency to form keloids have given variable results. We made a meta-analysis of the effects of P53 Arg72Pro polymorphism on keloid risk in the Chinese population by conducting searches of the published literature in Pubmed, Embase, CBMdisc, and CNKI databases up to June 2011. Six studies were included in the meta-analysis, with a total of 359 keloid cases and 493 healthy controls. Meta-analysis results, respectively in the PCR-reverse dot blot and PCR-RFLP subgroups, showed significant associations between P53 Arg72Pro polymorphism and susceptibility to keloid in the comparisons of Pro allele vs Arg allele (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.45-3.60; OR = 0.74, 95%CI = 0.56-0.98); Pro/Pro vs Pro/Arg + Arg/Arg (OR = 2.91, 95%CI = 1.88-4.53; OR = 0.54, 95%CI = 0.32-0.92); Pro/Pro vs Arg/Arg (OR = 2.79, 95%CI = 1.54-5.06; OR = 0.51, 95%CI = 0.28-0.92); Pro/Pro vs Pro/Arg (OR = 2.85, 95%CI = 1.75-4.63; OR = 0.57, 95%CI = 0.32-0.99). We conclude that the Pro allele of P53 Arg72Pro polymorphism is a risk factor for keloids in the Chinese population.

Association of p53 Arg72Pro and MDM2 SNP309 polymorphisms with glioma

Epidemiological studies of the association of variants p53 Arg72Pro and MDM2 single-nucleotide polymorphism 309 (SNP309) with glioma risk have produced inconsistent results. The aim of the current study was to evaluate the association of these 2 variants with glioma susceptibility using a meta-analysis approach. For p53 Arg72Pro, 10 case-control studies including 2587 glioma patients and 4061 unrelated controls were identified. The pooled odds ratios (ORs) for Arg/Pro heterozygotes and Pro/Pro homozygotes were 1.08 [95% confidence interval (95%CI) = 0.85-1.37] and 1.08 (95%CI = 0.85-1.36), respectively, when compared to Arg/Arg carriers. Under the dominant effect model, Pro allele carriers also showed no significantly elevated glioma risk (pooled OR = 1.11, 95%CI = 0.90-1.38), and similar results were found under the recessive-effect model (pooled OR = 1.17, 95%CI = 0.85-1.61). For variant MDM2 SNP309, 3 case-control studies including 606 cases and 309 controls were identified. A marginal association with glioma risk was found for heterozygous G/T carriers (pooled OR = 1.95, 95%CI = 1.00- 3.81), whereas homozygous G/G carriers showed an increased but not significantly elevated risk of glioma (pooled OR = 2.14, 95%CI = 0.71-6.45) compared with that of T/T homozygotes. We also found no significant association between the MDM2 SNP309 polymorphism and glioma risk (pooled OR = 1.86, 95%CI = 0.94-3.67 and pooled OR = 1.25, 95%CI = 0.62-2.56, respectively) under the dominant and recessive models. Taken together, the current data suggested that the 2 polymorphisms may not contribute to glioma susceptibility.

Abstract C109: Association of TP53 gene polymorphism with response to platinum-based doublet chemotherapy in non-small cell lung cancer patients.

Abstract Here we show that TP53 SNP is involved in chemotherapeutic responses in non-small cell lung cancer (NSCLC) patients. To identify polymorphisms in DNA repair genes that affect responses to platinum-based doublet chemotherapy, 640 NSCLC patients, who received platinum-based doublet chemotherapy and whose responses were evaluated by the Response Evaluation Criteria in Solid Tumors, were subjected to an association study between the response and genotypes for 30 SNPs in 27 DNA repair genes. Candidate SNPs were selected by screening of a discovery set of 201 cases and their associations were validated in an independent set of 439. Homozygotes for the TP53–72Pro allele of the TP53-Arg72Pro SNPs showed a better response rate (54.3%) than those for the TP53–72Arg allele (29.1%), and TP53–72Pro allele homozygotes had significantly longer progression-free and overall survivals than TP53–72Arg allele homozygotes. Minor allele carriers for a SNP, Lys940Arg, in the PARP1 (poly ADP-ribose polymerase 1) gene showed a better response rate to the regimen using paclitaxel (45.8%) than to the regimen using gemcitabine (10.5%). These results indicate that polymorphisms in the TP53 and PARP1 genes are involved in inter-individual differences in the response to platinum-based doublet chemotherapy in NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C109.

4.10 The p53 Pro72 Allele Potentially Increases the Poor Prognostic Significance of p53 Mutation in Chronic Lymphocytic Leukemia

4.10 The p53 Pro72 Allele Potentially Increases the Poor Prognostic Significance of p53 Mutation in Chronic Lymphocytic Leukemia

Association of the p53 codon 72 polymorphism with colorectal cancer in South West of Iran

The p53 tumor suppressor gene plays two important roles in genomic stability: blocking cell proliferation after DNA damage until it has been repaired, and starting apoptosis if the damage is too critical. Codon 72 exon4 polymorphism (Arg72Pro) of the P53 gene has been implicated in cancer risk. Various studies have been done to investigate the status of p53 at codon 72 for arginine (Arg) and proline (Pro) alleles in different populations and also the association of this codon 72 polymorphism with various tumors. Our objective was to investigate the possible association between P53 Arg72Pro polymorphism and susceptibility to colorectal cancer among Isfahan and Chaharmahal Va Bakhtiari (a part of south west of Iran) population. We investigated the status of p53 at codon 72 for Arg/Arg, Arg/Pro and Pro/Pro allele polymorphisms in blood samples from 145 colorectal cancer patients and 140 controls by Nested-PCR of p53 exon 4 and digestion with BstUI restriction enzyme and the DNA fragments were then resolved by electrophoresis in 2% agarose gel. The Pro allele was 279 bp, while the Arg allele was restricted into two fragments of 160 and 119 bp. Among the 145 colorectal cancer cases 49 cases (33.79%) were homozygous for the Arg72 allele (Arg/Arg), 18 cases (12.41%) were homozygous for the Pro72 allele (Pro/Pro) and 78 cases (53.8%) found in heterozygous (Arg/Pro). In conclusion, it can be said that p53Arg/Arggenotype may be correlated with possible increased risk of this kind of cancers in south west of Iran. Key words: Colorectal cancer, nested-PCR, p53 codon 72, polymorphism, Iran.