Abstract
Purpose
FOXP3 is a marker of the T regulatory (Treg) cell subset and drives its function and homeostasis. Its expression maintains the host immunosuppressive state that favors persistence of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL) appearance. The present study evaluated the effects of the rs3761548 and rs2232365 intronic single-nucleotide variants (SNVs) and their haplotypes on HPV infection and SIL diagnosis in HPV-infected and -uninfected women.
Methods
HPV DNA-based detection in cervical specimens was performed by PCR. FOXP3 variants were genotyped by PCR-restriction fragment length polymorphism and haplotype recombination sites were inferred for 208 HPV-infected and 218 HPV-uninfected women diagnosed or not with low- or high-grade intraepithelial lesions of cervix. Case–control analyses were carried out by logistic regression adjusted for several socio-demographic, sexual lifestyle, and clinical data.
Results
The homozygous genotype of the rs3761548 variants (A/A) (related to decreased FOXP3 expression) may exert a protective role against HPV infection in women (ORAj: 0.60; 95% CI 0.36–0.99; p = 0.049) and was an independent predictor of protection against HSIL development (ORAdj: 0.28; 95% CI 0.11–0.68; p = 0.006). In addition, the homozygous genotype (G/G) of the rs2232365 variants (related to increased FOXP3 expression) was independently associated with the HPV infection (ORAdj: 2.10; 95% CI 1.06–4.15; p = 0.033). Haplotype analysis revealed no significant associations in our study.
Conclusions
Our results reveal the significant and independent associations between FOXP3 genetic variants and susceptibility to HPV infection and SIL diagnosis and their role as biomarkers of HPV infection and cervical lesion management.
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Acknowledgements
The authors would like to thank the women who made this study possible, Intermunicipal Consortium of Health of the Middle Paranapanema (Cismepar), University Hospital and Clinic Center of State University of Londrina, Municipal Health Department of Londrina—PR, Brazil, and nurses of these health services for their technical assistance with patient screening and cervical sample collection.
Funding
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (470137/2013-4), Fundação Araucária—Programa Pesquisa para o SUS (34935.406.36850.19112012). Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001, and financial support for language editing from FAEPE/UEL-PUBLIC 2018.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Institutional Ethics Committee Involving Humans of the State University of Londrina, Londrina, PR, Brazil, CEP/UEL 133/2012, CAAE 05505912.0.0000.5231) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Cezar-dos-Santos, F., Ferreira, R.S., Okuyama, N.C.M. et al. FOXP3 immunoregulatory gene variants are independent predictors of human papillomavirus infection and cervical cancer precursor lesions. J Cancer Res Clin Oncol 145, 2013–2025 (2019). https://doi.org/10.1007/s00432-019-02951-x
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DOI: https://doi.org/10.1007/s00432-019-02951-x