FOXP3 immunoregulatory gene variants are independent predictors of human papillomavirus infection and cervical cancer precursor lesions

• Published in: Journal of cancer research and clinical oncology 2019-08, Vol.145 (8), p.2013-2025
• Main Authors: Cezar-dos-Santos, Fernando, Ferreira, Rodolfo Sanches, Okuyama, Nádia Calvo Martins, Trugilo, Kleber Paiva, Sena, Michelle Mota, Pereira, Érica Romão, Pereira, Ana Paula Lombardi, Watanabe, Maria Angelica Ehara, de Oliveira, Karen Brajão
• Format: Article
• Language: English
• Subjects: Adult; Brazil; Cancer Research; Case-Control Studies; Cervical cancer; Cervical Intraepithelial Neoplasia - diagnosis; Cervical Intraepithelial Neoplasia - genetics; Cohort Studies; Diagnosis; Female; Forkhead Transcription Factors - genetics; Foxp3 protein; Gene polymorphism; Genetic diversity; Genetic Predisposition to Disease; Genotype; Haplotypes; Health risk assessment; Hematology; Homeostasis; Human papillomavirus; Humans; Immunologic Factors - genetics; Immunoregulation; Infections; Internal Medicine; Lymphocytes T; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article – Cancer Research; Papillomaviridae - immunology; Papillomavirus Infections - diagnosis; Papillomavirus Infections - genetics; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Prognosis; Recombination; Restriction fragment length polymorphism; Risk Factors; Squamous Intraepithelial Lesions of the Cervix - diagnosis; Squamous Intraepithelial Lesions of the Cervix - genetics; Uterine Cervical Neoplasms - diagnosis; Uterine Cervical Neoplasms - genetics; Young Adult
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-019-02951-x

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 (OR Aj : 0.60; 95% CI 0.36–0.99; p  = 0.049) and was an independent predictor of protection against HSIL development (OR Adj : 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 (OR Adj : 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.