TP53 Polymorphisms Research Articles

Relationship between Helicobacter pylori detection and an increased risk of infection in childhood

The risk of developing gastric cancer is believed to be related to differences among Helicobacter pylori strains and the inflammatory responses mediated by host genetic factors. H. pylori infection is acquired at an early age and in the absence of appropriate antibiotic therapy, it generally persists for life. Tp53 gene regulates the transcription of several cytokines and chemokines involved in innate immunity and its action may be influenced by the presence of different H. pylori strains. The present study aimed to detect H. pylori in pediatric patients, to access Tp53 polymorphism at codon 72 and to correlate such findings with age and histopathological results. Three hundred and forty-two patients were analyzed. DNA from their gastric biopsies was extracted and the detection of H. pylori was performed through polymerase chain reaction assays, urease test and histopathologic examination. Allelic discrimination of SNP rs1042522 (Tp53) was performed by real-time polymerase chain reaction. Our results suggest a possible relationship between the presence of H. pylori and chronic gastritis in children and young patients, and showed a significant association between ageing and positivity for H. pylori. It was verified that patients aged < 10 years were 1.3 times more likely to have infection by H. pylori when compared with those aged > 10 years. Finally, no association was found between Tp53 polymorphisms and the presence of H. pylori.

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

p53 is involved in stress response, metabolism and cardiovascular functioning. The C-allele of rs1042522 in the gene encoding for p53 is associated with longevity and cancer. In this study, we aimed to investigate the association of rs1042522 with changes in blood pressure, BMI and waist circumference using a longitudinal approach. Rs1042522 was analyzed in two longitudinal studies; the Doetinchem Cohort Study (DCS) and the Botnia Prospective Study (BPS). Changes in quantitative traits over time were investigated according to rs1042522 genotypes. An association between rs1042522 and changes in diastolic blood pressure (DBP) in the DCS over time was observed (P=0.004). Furthermore, a borderline significant association was detected with changes in waist circumference over time (P=0.03). These findings were also observed in the BPS (P=0.02 and P=0.05). The C/C-genotype (Pro/Pro) showed the most moderate time-related increase for the studied endpoints. Furthermore, data from the BPS suggested that the C/C-genotype protects against increases in glucose levels over time at 30 and 60 min during oral glucose tolerance test (P=0.01 and P=0.02). In conclusion, we found an association between the C/C-genotype of rs1042522 and changes in DBP and waist circumference over time. This might contribute to the longevity phenotype observed for the same genotype by others.

Polymorphisms of TP53 are markers of bladder cancer vulnerability and prognosis

ObjectivesWe have reported previously that the TP53 codon72 polymorphism (rs1042522) is associated with the incidence and invasiveness of bladder cancer in a Han Chinese population. Using an enlarged sample, we investigated the role of rs1042522 and of tagSNPs that were predicted to be in linkage disequilibrium with codon72 in relation to the incidence, invasiveness, and prognosis of bladder cancer. Methods and materialsA sample of 201 patients and 311 controls without cancer were genotyped for 5 tagSNPs using tetra-primer ARMS and/or an allele-specific PCR technique. ResultsThe genotyped data were analyzed using Haploview 4.2, and a 10,000-permutation test showed that the rs9895829G allele (P = 0.003) and the rs1788227C allele (P = 0.027) were both associated with the incidence of bladder cancer. With respect to haplotype associations, after the data were adjusted for age, the haplotypes GTT (P = 0.001) and GGTC (P < 0.001) were correlated with a low incidence of bladder cancer. In contrast, none of the TP53 haplotypes were associated significantly with high tumor grade or muscle invasiveness. On the basis of Cox regression analysis, haplotype CGCC and invasiveness were associated with cancer-related death. Structural equation modeling showed that haplotypes GGCC and CGCC played opposing roles with respect to bladder cancer-related death; haplotype GGCC was a protective factor, whereas haplotype CGCC was a risk factor. ConclusionsThe TP53 codon72 polymorphism appears to play a crucial role in determining the association between TP53 haplotype and the incidence and prognosis of bladder cancer. Further functional assays to confirm whether these TP53 haplotypic variants interact with the proteins N-Myc and NDRG is necessary.

TP53 mutations and Polymorphisms in Primary Myelofibrosis,

Abstract 3840▪▪This icon denotes a clinically relevant abstract Background:Patients with myeloproliferative neoplasms (MPN) harbor a multitude of somatic mutations involving JAK2, MPL, LNK, CBL, TET2, ASXL1, IDH1, IDH2, EZH2, DNMT3A, IKZF1 and TP53. None of these mutations have been consistently traced back to the ancestral clone and most of them are currently believed to represent secondary genetic events. The higher prevalence of IDH, LNK, IKZF1 and TP53 mutations in blast-phase MPN, as opposed to chronic-phase disease, suggests their pathogenetic contribution to leukemic transformation (Harutyunyan A, et al. N Engl J Med. 2011;364:488). We examined this possibility for TP53 mutations or its SNPs in chronic-phase PMF; TP53 SNPs involving codon 72 have been associated with increased risk in the development of several cancers. Methods:Mayo Clinic MPN database was utilized to identify adult patients (>18 years) with chronic-phase PMF. Study eligibility criteria included availability of bone marrow histology and cytogenetic information at time of referral. In addition, all patients were annotated for IDH, MPL and JAK2 mutational status. Patients with blast-phase disease at the time of their referral were excluded from the study. DNA from bone marrow or peripheral blood was extracted using conventional methods and amplified with one set of primers covering TP53 exons 4 through 9. The amplification products were then sequenced with eight primers using the Big Dye Terminator sequencing kit v1.1 (Applied Biosystems, Foster City, CA) and the ABI 3130xl Genetic Analyzer. Sequences were examined for mutations by the Sequencher software (Gene Codes, Ann Arbor, MI). Any mutation found was confirmed with a second PCR and sequencing reaction. A mutation was considered to be any sequence other than genomic reference sequence NC_000017.10 or a well documented polymorphism such as the rs1042522 in exon 4. Mutations were compared with the IARC p53 Database (http://www-p53.iarc.fr/) and/or the TP53 Mutation Database (http://p53.free.fr/index.html) to determine if the mutation had been reported before. Results I:Baseline characteristics and clinical course A total of 107 patients with chronic-phase PMF were studied. Median age at time of referral was 64 years (range 32–81) and 71% were males. DIPPS-plus risk assignment was low in 13%, intermediate-1 in 15%, intermediate-2 in 38% and high in 34%. Karyotype was normal in 70 (65%) patients, favorable in 26 (24%) and unfavorable in 11 (10%). JAK2, MPL and IDH mutations were detected in 62 (58%), 7 (7%) and 6 (6%) cases, respectively. To date, 74% of patients had died and 15% had documented leukemic transformation. Results II:TP53 mutations/polymorphisms and their clinical relevance TP53 mutations were discovered in only 4 (4%) cases: i) E204E; GAG>GAA (silent exon 6); ii) G245D; GGC>GAC (exon 7); iii) R175H; CGC>CAC (exon 5); and iv) six base insert (GGCGAG) after bp13767 (exon 6). There was no significant difference in presenting features or survival between TP53 mutated and unmutated cases. None of the four patients with TP53 mutation incurred leukemic transformation. TP53 exon 4 SNPs data for codon 72 was available on 104 patients and included 58 (56%) patients with homozygous Arg72Arg, 34 (33%) patients with heterozygous Pro72Arg and 12 (11%) patients with homozygous Pro72Pro. Allele frequencies were 0.7 for G (corresponding to arginine) and 0.3 for C (corresponding to proline), which is similar to the general population (0.65 and 0.35 respectively). There were no significant differences among the three codon 72 genotypes in terms of presenting characteristics or survival. Conclusions:TP53 mutations are infrequent in chronic phase PMF. A higher number of informative cases are needed to accurately define their phenotypic or prognostic effects. We are currently analyzing more cases in this regard. On the other hand, TP53 polymorphisms at codon 72 do not appear to influence phenotype or prognosis in chronic-phase PMF. Disclosures:No relevant conflicts of interest to declare.

TP53 mutations and polymorphisms in primary myelofibrosis

A total of 107 patients with chronic-phase primary myelofibrosis (PMF) were screened for TP53 mutations, which were detected in 4 (4%) cases: (i) E204E; GAG>GAA (silent exon 6); (ii) G245D; GGC>GAC (exon 7); (iii) R175H; CGC>CAC (exon 5); and (iv) six base insert (GGCGAG) after bp13767 (exon 6). Three (75%) of the four TP53-mutated cases also carried JAK2V617F whereas none were positive for MPL or IDH mutations. Two of the four TP53 mutated cases were also screened for TET2, ASXL1, DNMT3A, and EZH2 mutations and were negative. There was no significant difference in presenting features or survival between TP53 mutated and unmutated cases. TP53 exon 4 single nucleotide polymporphism (SNPs) data for codon 72 were available on 104 patients and included 56% with homozygous Arg72Arg, 33% with heterozygous Pro72Arg, and 11% with homozygous Pro72Pro. There were no significant differences among the three codon 72 genotypes in terms of presenting characteristics or survival.

Evidence that polymorphisms in detoxification genes modulate the susceptibility for sporadic medullary thyroid carcinoma

Polymorphic low-penetrance genes have been consistently associated with the susceptibility to a series of human tumors, including differentiated thyroid cancer. To determine their role in medullary thyroid cancer (MTC), we used TaqMan SNP method to genotype 47 sporadic MTC (s-MTC) and a control group of 578 healthy individuals for CYP1A2*F, CYP1A1m1, GSTP1, NAT2 and 72TP53. A logistic regression analysis showed that NAT2C/C (OR=3.87; 95% CI=2.11-7.10; P=2.2×10(-5)) and TP53C/C genotypes (OR=3.87; 95% CI=1.78-6.10; P=2.8×10(-4)) inheritance increased the risk of s-MTC. A stepwise regression analysis indicated that TP53C/C genotype contributes with 8.07% of the s-MTC risk. We were unable to identify any relationship between NAT2 and TP53 polymorphisms suggesting they are independent factors of risk to s-MTC. In addition, there was no association between the investigated genes and clinical or pathological features of aggressiveness of the tumors or the outcome of MTC patients. In conclusion, we demonstrated that detoxification genes and apoptotic and cell cycle control genes are involved in the susceptibility of s-MTC and may modulate the susceptibility to the disease.

A single-nucleotide polymorphism in TP53 may be a genetic risk factor for Iranian patients with idiopathic male infertility

Male infertility is a heterogeneous disorder that contributes to the impairment of spermatogenesis. The purpose of this study was to assess whether tumour suppressor p53 gene (Tp53) polymorphism is associated with idiopathic male infertility in the Iranian population. The prevalence of G → C substitution at codon 72 in exon 4 was determined in 110 idiopathic infertile azoo-/oligospermic patients and 180 fertile healthy control men. PCR-restriction fragment polymorphism analysis was employed to determine the genotypes. PCR amplicons were subjected to restriction digestion with Bstu1 and separated by gel electrophoresis. The Arg/Arg genotype was found more frequently among men with idiopathic infertility (32.7%) than among controls (17.7%). No significant difference was observed between Pro/Pro genotype and Arg/Arg + Arg/Pro genotypes among men with idiopathic infertility and controls (P = 0.11; OR: 0.36; 95% CI: 0.36-1.10). In contrast, a significant difference was observed in the comparison of the Arg/Arg genotype and Arg/Pro + Pro/Pro genotypes among patients and controls (P = 0.004; OR: 2.25; 95% CI: 1.29-3.90). Allele frequency evaluation suggested a significantly higher incidence of the Arg allele among infertile men compared with controls (56% versus 44%; OR: 1.6; 95% CI: 0.92-2.80). In conclusion, arginine allele appears to be at greater risk of developing idiopathic infertility in Iranian men.

Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis

Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. The immunoprofile that correlates with wild-type TP53, however, is not as clear. In particular, the significance of completely negative immunostaining is controversial. The aim of this study was to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. A total of 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, 2 malignant mesodermal mixed tumors (carcinosarcomas), 2 low-grade serous carcinomas, 4 clear cell carcinomas, 1 well-differentiated endometrioid carcinoma, and 5 carcinomas with mixed epithelial differentiation) were analyzed for TP53 mutations by nucleotide sequencing (exons 4–9), and subjected to immunohistochemical analysis of p53 expression. Thirty six tumors contained functional mutations and 13 had wild type TP53. Five tumors were found to harbor known TP53 polymorphism and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a wide range of immunolabeling patterns, with the most common pattern showing ≤10% of positive cells in 6 cases (46%). Mutant TP53 was associated with 60–100% positive cells in 23 cases (64% of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (0% cells staining) had a mutation of TP53 in 65% of cases and wild-type TP53 in 11%. Combining two immunohistochemical labeling patterns associated with TP53 mutations (0% and 60–100% positive cells), correctly identified a mutation in 94% of cases (P<0.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a strong and diffuse pattern of p53 expression (in greater than 60% of cells), complete absence of p53 immunoexpression is commonly associated with a TP53 mutation. Accordingly, this latter pattern, unlike low-level expression (10–50% cells), should not be construed as indicative of wild-type TP53.

TP53 codon 72 polymorphisms in favorable histology Wilms tumors

In Wilms tumor (WT), mutations in the gene encoding p53, TP53, are correlated with anaplasia; however TP53 variants have not been studied in favorable histology (FH) WTs. A single nucleotide polymorphism of TP53 encoding either arginine or proline at codon 72 is suggested to alter in vitro p53 behavior. Therefore, we analyzed tissue from 23 consecutive patients with FHWT to determine allelic and genotypic frequencies of Pro72 and Arg72 variants and correlate this with clinical outcomes. Interestingly, our cohort showed a statistically significant over-representation of the Arg allele and Arg/Arg genotype. However, the genotypic and allelic frequencies showed no significant correlation with age, stage, or disease recurrence.

Coordination ofTP53Abnormalities in Breast Cancer: Data from Analysis ofTP53Polymorphisms, Loss of Heterozygosity, Methylation, and Mutations

We have studied whether TP53 rs1042522, rs17878362, and rs1625895 alleles having a protective effect against breast cancer (BC) will be lost in tumors, whereas those allowing disease development will be retained. Analysis of TP53 polymorphisms was performed in blood leukocytes and tumors from 80 Caucasian BC patients. In addition, TP53 loss of heterozygosity (LOH), methylation, and mutations were studied in tumor DNA of BC individuals with loss of alleles of TP53 polymorphisms. In breast tumors of patients heterozygous for TP53 polymorphisms, we detected loss of rs1042522 C and G and rs17878362 A2 alleles; however, the loss of the C allele was preferential. We found that loss of TP53 alleles, namely rs1042522 C, has been caused by an LOH mechanism, namely TP53 deletions, whereas TP53 point mutations frequently occurred in the retained G allele (p=0.03). In addition, we showed that BC patients with rs1042522 CC genotype were characterized by only unifocal tumors and decreased frequency of lymph node metastases (p=0.03). Taken together, we showed the preferential loss of the rs1042522 C allele, which is protective against BC progression, in breast tumors. Also, the loss of the C allele, which encodes p53 protein with the best DNA repair capability according to literature data, may create prerequisites for mutations, but not for methylation in a retained G variant, as we found here. However, these results need to be confirmed because of the limited statistical power of the present study and the small sampling.

Impact of TP53 Codon 72 and MDM2 Promoter 309 Allelic Dosage in a Moroccan Population with Hepatocellular Carcinoma

Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been shown to play a role in the predisposition to many cancers. However, these findings were inconsistent in other tumor types, and ethnicity is suspected to be a critical factor influencing the effects of these SNPs on the cancer risk. The aim of the present study was to investigate whether these functional SNPs were associated with an enhanced risk of liver tumorigenesis in Moroccan patients. We have genotyped both polymorphisms in 96 patients with hepatocellular carcinoma (HCC) and 222 controls without HCC matched for age, gender and ethnicity by PCR-RFLP confirmed by sequencing. A joint effect between the MDM2 and TP53 polymorphisms and an increased risk of liver cancer was detected, with the odds ratio for the presence of both MDM2 309GG and TP53 72Pro/Pro genotypes being 10 (95% confidence interval 0.39-255.55). Interestingly, a significant increase in the HCC risk was observed when at least two deleterious alleles were present, indicating an allele dosage effect. There was no evidence for any association with early age of HCC onset when deleterious alleles of MDM2 SNP309 and TP53 Arg72Pro where present. Our findings suggest that the combination of TP53 72Pro and MDM2 309G polymorphisms enhance the risk of developing HCC. These results deserve further confirmation in other populations.

Candidate gene studies in gallbladder cancer: A systematic review and meta-analysis

Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene-disease association using fixed and random effect models. Meta-regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility except TP53 (rs1042522) polymorphism. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene-gene, gene-environment interactions and high-risk haplotypes.

Sex-specific effect of the TP53 PIN3 polymorphism on cancer risk in a cohort study of TP53 germline mutation carriers

Germline mutations in the tumor suppressor gene TP53 occur in the majority of families with Li-Fraumeni syndrome, who are at an increased risk for a wide spectrum of early onset cancers. Several genetic polymorphisms in TP53 modify its effect on cancer risk. While some studies indicate that the TP53 PIN3 deletion allele (D) accelerate tumor onset in carriers with TP53 germline mutations, other studies have shown that the TP53 PIN3 insertion allele (I) confers a significantly higher risk of developing cancer than D allele. To further determine the effects of the TP53 PIN3 polymorphism on cancer development among TP53 germline mutations and to evaluate if those are differenence between male and female carriers, we studied a total of 152 germline mutation carriers with available DNA samples that can be used for genotyping. Our results indicate that the TP53 PIN3 polymorphism has a sex-specific effect on the risk of cancer in TP53 mutation carriers, conferring cancer risk in men (P=0.0041) but not women with DI or II genotypes.

A single‐nucleotide polymorphism in the TP53 and MDM‐2 gene modifies breast cancer risk in an ethnic Arab population

Breast cancer is the most common oncological disease in women worldwide. Genetic predisposition to breast cancer can be associated with single-nucleotide polymorphisms (SNPs), which are observed in many women. Such gene polymorphisms, in combination with nutritional and environmental factors, can affect breast cancer development. The tumor suppressor TP53 and its negative regulator MDM2 play crucial roles in carcinogenesis. Previous case-control studies have revealed that TP53 72Arg > Pro and MDM2 309T > G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and breast cancer susceptibility in the Saudi population has not been explored. In this study, we performed a case-control study of patients with breast cancer and healthy controls in a Saudi population using TaqMan-based real-time PCR. We found an increased breast cancer risk associated with the MDM2 GG [odds ratio (OR) = 2.79, 95% confidence interval (CI) = 2.04-3.92] and TG [OR = 1.43, 95% CI = 1.12-2.02] genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 2.19, 95% CI = 1.54-3.06) compared with the Arg/Arg genotype. The gene-gene interaction of MDM2 and TP53 polymorphisms increased breast cancer risk in a multiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 7.71, 95% CI = 3.49-17.54). These findings suggest that polymorphisms of MDM2 and TP53 genes may be a genetic modifier for developing breast cancer in this ethnic population in the Arab world.

Tumor Protein p53 Gene Polymorphism and Developmental Competence of Embryos Derived from in Vitro Fertilization in Old-aged and Long-term Infertile Japanese Black Cows

The present study analyzed tumor protein p53 gene (TP53) polymorphism as a factor in uterine implantation and establishment of pregnancy in four old-aged Japanese Black cows with long-term infertility. They had G allele or A allele in exon 6 of the gene. Oocytes were collected from these females using ovum pick up (OPU) and fertilized in vitro. Only some of the oocytes from individuals having G allele had developmental competence to the blastocyst stage, while no oocytes having the A allele had the competence to develop to the blastocyst stage. In conclusion, we suggest that a cause of long-term infertility in old-aged Japanese Black cows may be a polymorphism of TP53 affecting the competence of embryonic development.

The TP53 gene polymorphisms and survival of sporadic breast cancer patients

The TP53 gene polymorphisms, Arg72Pro and PIN3 (+16 bp), can have prognostic and predictive value in different cancers including breast cancer. The aim of the present study is to investigate a potential association between different genotypes of these polymorphisms and clinicopathological variables with survival of breast cancer patients in Croatian population. Ninety-four women with sporadic breast cancer were retrospectively analyzed. Median follow-up period was 67.9 months. The effects of basic clinical and histopathological characteristics of tumor on survival were tested by Cox's proportional hazards regression analysis. The TNM stage was associated with overall survival by Kaplan-Meier analysis, univariate, and multivariate Cox's proportional hazards regression analysis, while grade was associated with survival by Kaplan-Meier analysis and univariate Cox's proportional hazards regression analysis. Different genotypes of the Arg72Pro and PIN3 (+16 bp) polymorphisms had no significant impact on survival in breast cancer patients. However, in subgroup of patients treated with chemotherapy without anthracycline, the A2A2 genotype of the PIN3 (+16 bp) polymorphism was associated with poorer overall survival than other genotypes by Kaplan-Meier analysis (P = 0.048). The TP53 polymorphisms, Arg72Pro and PIN3 (+16 bp), had no impact on survival in unselected sporadic breast cancer patients in Croatian population. However, the results support the role of the A2A2 genotype of the PIN3 (+16 bp) polymorphism as a marker for identification of patients that may benefit from anthracycline-containing chemotherapy.

Genetic polymorphisms of TP53 and FAS promoter modulate the progression of coronary artery disease after coronary artery bypass grafting: a gender-specific view

Progression of coronary artery disease (CAD) after primary coronary artery bypass grafting (CABG) is frequent and may lead to recurrent symptoms. Various data indicate that apoptosis is the main event occurring during development and progression of atherosclerotic plaque. Plaque vascular smooth muscle cells (VSMCs) are more sensitive than regular VSMCs to TP53-mediated apoptosis. We investigated EDTA blood of 192 patients (18% female, age 60.9 ± 7.4 years) who had primary CABG more than 5 years ago. CAD progression was defined as clinical endpoints: re-operation (n = 88; 46%), catheter re-intervention (n = 58; 30%), or angina at follow-up (n = 89; 46%). Apoptotic gene polymorphisms (Toll-like receptor 2 A753G, FAS ligand C-844T, FAS promoter G-670A, TP53 Arg72Pro, and CD14 C-260T) were investigated by PCR-RFLP and compared to healthy controls (n = 200, 24% female, age 63.4 ± 5.4). Gender-specific analysis was carried out. Heterozygous, homozygous and wild-type expression of all five genetic polymorphisms showed almost identical distribution between patients with CAD and healthy controls. Looking at clinical endpoints, with GG expression of Toll-like receptor 2 polymorphism and GG expression of FAS promoter polymorphism, results showed a relative increased risk (p = 0.09) for recurrent symptoms and re-intervention. Patients with FAS promoter polymorphism with AA expression had an increased risk of suffering from recurrent symptoms (n = 28, p = 0.04). We found that patients with homozygous expression of TP53 polymorphisms (n = 3, all male) were prone to needing re-intervention after prior CABG (p = 0.03), but not re-operation. Over a period up to 15 years, the re-intervention rate was significantly different in homozygous genotypes of FAS LG, FAS promoter and TP53. Patients presenting with polymorphisms of FAS LG, FAS promoter and TP53 have an increased risk of CAD progression, as they have a higher rate of re-interventions.

Genetic polymorphisms of TP53 and FAS promoter modulate the progression of coronary artery disease after coronary artery bypass grafting

Introduction: Progression of coronary artery disease (CAD) after primary coronary artery bypass grafting (CABG) is frequent and may lead to recurrent symptoms. Apoptosis is a main event occurring during development and progression of atherosclerotic plaque, and earlier studies suggest that TP53 may contribute to CAD progression. We investigated the influence of TP53 and other apoptotic gene polymorphisms upon the risk of CAD progression.

Short Communication Influence of Arg72Pro polymorphisms of TP53 on the response of buccal cells to radiotherapy

Polymorphisms in the TP53 gene codon 72 (Arg72Pro) influence apoptosis induction and DNA damage repair. We evaluated how variants of protein p53 (p53Arg and p53Pro) affect cell death and DNA damage repair by analyzing the frequencies of karyorrhexis and micronuclei. There were significant differences in the frequency of karyorrhexis between the three p53 genotypes (Arg/Arg, Arg/Pro, and Pro/Pro), between samples taken before and after radiotherapy, and between patients and controls. The frequency of micronucleated cells increased significantly after radiotherapy. There were no significant differences in the micronucleus frequency in healthy tissues of these patients compared to controls, or in the comparisons between the three genotypes. We conclude that Arg72Pro polymorphism influences cell apoptotic capacity. This is the first study investigating karyorrhexis and micronuclei, as indicators of apoptosis after radiotherapy, and how these indicators are influenced by the TP53 polymorphism Arg72Pro.

Association between polymorphisms in RAPGEF1, TP53, NRF1 and type 2 diabetes in Chinese Han population

Type 2 diabetes is a common complex disorder with environmental and genetic components. The aim of the present study was to investigate the association between the polymorphisms of RAPGEF1, TP53 and NRF1 and the risk of type 2 diabetes in the Chinese Han population. We genotyped rs11243444 ( RAPGEF1), rs1042522 ( TP53) and rs1882095 ( NRF1) in a case-control study, including 273 type 2 diabetes and 247 healthy controls. A significant association was found in a variant of TP53 (rs1042522, odd ratio (OR) = 1.28, 95% confidence interval (CI) = 1.00–1.64; P = 0.046), whereas polymorphisms in RAPGEF1, NRF1 were not associated with the risk of type 2 diabetes. Furthermore, a potential gene–gene interaction showed the odds of being affected with type 2 diabetes was 2.54 times greater in subjects with the TP53 (rs1042522) and RAPGEF1 (rs11243444) risk alleles than those without either (95% CI = 1.34–4.81; P = 0.004) and the NRF1 gene polymorphism reached significance when paired with TP53:(OR = 3.87, 95% CI = 1.87–8.40; P = 0.0006). We demonstrated that the polymorphism in TP53 (rs1042522) was associated with type 2 diabetes, and that potential interaction of TP53 (rs1042522) and RAPGEF1 (rs11243444), or NRF1 (rs1882095) increased the risk of type 2 diabetes.