Elevated serum expression of p53 and association of TP53 codon 72 polymorphisms with risk of cervical cancer in Bangladeshi women

Differential expression of p53 has been reported in cervical cancer, primarily in tumor tissue biopsies. In this study, we examined the association of TP53 codon 47 and codon 72 polymorphisms and serum level expression of p53 in cervical cancer patients (n = 129) and healthy controls (n = 122). We found elevated levels of serum p53 protein levels in cervical cancer patients (p = 0.0442) compared to healthy controls. Moreover, we found higher levels of serum p53 in patients with grade-III tumor (p = 0.001) compared to healthy controls. Examination of SNPs showed TP53 Arg/Pro heterozygosity (adjusted OR = 2.126, 95% CI = 1.181–3.827, p = 0.012), Pro/Pro mutant homozygosity (adjusted OR = 3.564, 95% CI = 1.647–7.713, p = 0.001), along with the combined genotype (Arg/Pro+Pro/Pro) (adjusted OR 2.542, 95% CI = 1.517–4.260, p<0.001) significantly increases the risk of cervical cancer. Expression quantitative trait analysis revealed no significant association with protein expression. Our results represent for the first time the upregulation of serum p53 in cervical cancer in Bangladeshi women and supports the association of TP53 codon 72 polymorphisms with cervical cancer.

Differential Transcriptional Regulation of Polymorphic p53 Codon 72 in Metabolic Pathways

p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells. To investigate the functional differences of polymorphic p53 codon 72, we constructed isogenic lines encoding each polymorphic p53 codon 72 based on induced pluripotent stem cells, which can endogenously express each polymorphic p53 protein only, encoding either the arginine 72 (R72) variant or proline 72 (P72) variant, respectively. We found that there was no significant functional difference between P72 and R72 cells in growth arrest or apoptosis as a representative function of p53. In the comprehensive analysis, the expression pattern of the common p53 target genes, including cell cycle arrest or apoptosis, was also increased regardless of the polymorphic p53 codon 72 status, whereas the expression pattern involved in metabolism was decreased and more significant in R72 than in P72 cells. This study noted that polymorphic p53 codon 72 differentially regulated the functional categories of metabolism and not the pathways that determine cell fate, such as growth arrest and apoptosis in cells exposed to genotoxic stress.

SARS-CoV-2: Understanding the Transcriptional Regulation of ACE2 and TMPRSS2 and the Role of Single Nucleotide Polymorphism (SNP) at Codon 72 of p53 in the Innate Immune Response against Virus Infection

Human ACE2 and the serine protease TMPRSS2 of novel SARS-CoV-2 are primary entry receptors in host cells. Expression of these genes at the transcriptional level has not been much discussed in detail. The ISRE elements of the ACE2 promoter are a binding site for the ISGF3 complex of the JAK/STAT signaling pathway. TMPRSS2, including IFNβ, STAT1, and STAT2, has the PARP1 binding site near to TSS either up or downstream promoter region. It is well documented that PARP1 regulates gene expression at the transcription level. Therefore, to curb virus infection, both promoting type I IFN signaling to boost innate immunity and prevention of virus entry by inhibiting PARP1, ACE2 or TMPRSS2 are safe options. Most importantly, our aim is to attract the attention of the global scientific community towards the codon 72 Single Nucleotide Polymorphism (SNP) of p53 and its underneath role in the innate immune response against SARS-CoV-2. Here, we discuss codon 72 SNP of human p53′s role in the different innate immune response to restrict virus-mediated mortality rate only in specific parts of the world. In addition, we discuss potential targets and emerging therapies using bioengineered bacteriophage, anti-sense, or CRISPR strategies.

Associations of TP53 codon 72 polymorphism with complications and comorbidities in patients with type 1 diabetes

Wild-type TP53 plays an important role in the regulation of immune response and systemic inflammation. In type 1 diabetes (T1D), TP53 pathways are upregulated and an increased susceptibility to apoptosis is observed. We hypothesize that TP53 codon 72 polymorphism could be associated with complications and comorbidities in patients with T1D. We have investigated the associations of the TP53 codon 72 polymorphism with the T1D complications and comorbidities (retinopathy, nephropathy, hypertension, dyslipidemia, autoimmune thyroiditis, and celiac disease) in 350 patients. The key results of our approach are as follows: (1) In diabetic subjects, the Pro/Pro genotype is associated with an increased risk of microvascular complications, dyslipidemia, and celiac disease; (2) the Arg/Arg variant is associated with a decreased risk of autoimmune thyroiditis and celiac disease; (3) the Pro allele is associated with an increased risk of dyslipidemia, autoimmune thyroiditis, and celiac disease. Although further studies are required, our results for the first time indicate that the TP53 codon 72 polymorphism could be considered a genetic marker to predict the increased susceptibility to some T1D complications and comorbidities. Key messages We analyzed the TP53 codon 72 polymorphism in patients with T1D. Pro/Pro genotype is associated with an increased risk of microvascular complications, dyslipidemia, and celiac disease. The Arg/Arg variant is associated with a decreased risk of autoimmune thyroiditis and celiac disease. The Pro allele is associated with an increased risk of dyslipidemia, autoimmune thyroiditis, and celiac disease.

Relationship between TP53 and interleukin-6 gene variants and the risk of types 1 and 2 diabetes mellitus development in the Kermanshah province

Diabetes mellitus (DM) is a metabolic disorder that results from insufficient secretion or insulin resistance, or both. Insulin secretion deficiency leads to chronic hyperglycemia along with impaired metabolism of proteins, lipids, and carbohydrates. This study aimed to investigate the TP53 gene SNP (single nucleotide polymorphism) rs1042522 genotype and the interleukin-6 (IL-6) gene SNP rs1800795 genotype in DM and control groups. This study was performed on 70 patients with type 1 DM, 100 patients with type 2 DM without related complications, 66 control subjects for type 1 DM, and 95 control subjects for type 2 DM. The control groups were matched regarding age and gender and did not have a familial relationship with the patient groups. All the subjects were residents of Kermanshah, located in the western part of Iran. Polymorphisms of TP53 and IL-6 genes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Lipid profile, fasting blood glucose, and HbA1c were measured using the ELISA and immunoturbidometric methods. The frequency of genotypes (CC, CG, GG) of the TP53 gene codon 72 in type 1 DM and its control group were significantly different (P= 0.013). Likewise, the frequency of genotypes (CC, CG, GG) of the TP53 gene codon 72 was significantly different between type 2 DM and control groups (P <0.001). The frequency of genotypes (GG, GC, CC) of G174C polymorphisms in the IL-6 gene was different between type 1 DM and control group as well as between type 2 DM and its control group, but it was not statistically significant. SNP rs1042522 genotypes in the dominant form (CG + GG vs. CC) (OR= 3.880; P < 0.001) and alleles G vs. C alleles (OR= 0.384; P < 0.001) increased the risk of type 2 DM significantly. There was no significant difference between type 1 and type 2 DM groups and respected control groups regarding the frequency of the IL-6 gene SNP rs1800795 alleles. The G allele of SNP rs1042522 encoding the TP53 gene increases the risk of developing DM in the population of the Kermanshah province, Iran.