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Evidence for an epistatic effect between TP53 R72P and MDM2 T309G SNPs in HIV infection: a cross-sectional study in women from South Brazil.

ABSTRACT: To investigate the associations of TP53 R72P and MDM2 T309G SNPs with HPV infection status, HPV oncogenic risk and HIV infection status.Cross-sectional study combining two groups (150 HIV-negative and 100 HIV-positive) of women.Data was collected using a closed questionnaire. DNA was extracted from cervical samples. HPV infection status was determined by nested-PCR, and HPV oncogenic risk group by Sanger sequencing. Both SNPS were genotyped by PCR-RFLP. Crude and adjusted associations involving each exposure (R72P and T309G SNPs, as well as 13 models of epistasis) and each outcome (HPV status, HPV oncogenic risk group and HIV infection) were assessed using logistic regression.R72P SNP was protectively associated with HPV status (overdominant model), as well as T309G SNP with HPV oncogenic risk (strongest in the overdominant model). No epistatic model was associated with HPV status, but a dominant (R72P over T309G) protective epistatic effect was observed for HPV oncogenic risk. HIV status was strongly associated (risk factor) with different epistatic models, especially in models based on a visual inspection of the results. Moreover, HIV status was evidenced to be an effect mediator of the associations involving HPV oncogenic risk.We found evidence for a role of R72P and T309G SNPs in HPV status and HPV oncogenic risk (respectively), and strong associations were found for an epistatic effect in HIV status. Prospective studies in larger samples are warranted to validate our findings, which point to a novel role of these SNPs in HIV infection.

SUBMITTER: Hartwig FP

PROVIDER: S-EPMC3938491 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Evidence for an epistatic effect between TP53 R72P and MDM2 T309G SNPs in HIV infection: a cross-sectional study in women from South Brazil.

Hartwig Fernando Pires FP Entiauspe Ludmila Gonçalves LG Nunes Emily Montosa EM Rodrigues Fernanda Martins FM Collares Tiago T Seixas Fabiana Kömmling FK da Silveira Mariângela Freitas MF

PloS one 20140228 2

<h4>Objective</h4>To investigate the associations of TP53 R72P and MDM2 T309G SNPs with HPV infection status, HPV oncogenic risk and HIV infection status.<h4>Design</h4>Cross-sectional study combining two groups (150 HIV-negative and 100 HIV-positive) of women.<h4>Methods</h4>Data was collected using a closed questionnaire. DNA was extracted from cervical samples. HPV infection status was determined by nested-PCR, and HPV oncogenic risk group by Sanger sequencing. Both SNPS were genotyped by PCR ...[more]

PMID: 24586820

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Project description:BackgroundHepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. Previous work showed that in the western part of North Africa, a region of low incidence of HCC, mutations are scarce for this tumor type. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, thus, to characterize DNA methylation in HCC from North-African patients.MethodsA set of 11 loci was investigated in a series of 45 tumor specimens using methylation-specific and combined-bisulfite restriction assay PCR. Results obtained on clinical samples were subsequently validated in liver cancer cell lines.ResultsDNA methylation at tumor suppressor loci is significantly higher in samples displaying chromosome instability. More importantly, DNA methylation was significantly higher in Arg/Arg when compared to Pro/Pro genotype carriers at codon 72 rs1042522 of TP53 (65% vs 20% methylated loci, p = 0.0006), a polymorphism already known to affect somatic mutation rate in human carcinomas. In vitro experiments in cell lines indicated that enzymes controlling DNA methylation were differentially regulated by codon 72 Arg or Pro isoforms of p53. Furthermore, the Arg72-carrying version of p53 was shown to re-methylate DNA more rapidly than the pro-harboring isoform. Finally, Pro-carrying cell lines were shown to be significantly more resistant to decitabine treatment (two-fold, p = 0.005).ConclusionsOur data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC. It suggests, in addition, that rs1042522 genotype may predict sensitivity to epigenetic-targeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, therefore, apply essentially to population living in similar areas. Surveys on populations submitted to highly mutagenic conditions as perinatally-acquired chronic hepatitis B or aflatoxin B1 exposure remained to be conducted to validate our observations as a general model.

Dataset Information

Evidence for an epistatic effect between TP53 R72P and MDM2 T309G SNPs in HIV infection: a cross-sectional study in women from South Brazil.

Publications

Evidence for an epistatic effect between TP53 R72P and MDM2 T309G SNPs in HIV infection: a cross-sectional study in women from South Brazil.

Similar Datasets

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