Common Variants in Immune and DNA Repair Genes and Risk for Human Papillomavirus Persistence and Progression to Cervical Cancer

• Published in: The Journal of infectious diseases 2009-01, Vol.199 (1), p.20-30
• Main Authors: Wang, Sophia S., Bratti, M. Concepcion, Rodríguez, Ana Cecilia, Herrero, Rolando, Burk, Robert D., Porras, Carolina, González, Paula, Sherman, Mark E., Wacholder, Sholom, Lan, Z. Elizabeth, Schiffman, Mark, Chanock, Stephen J., Hildesheim, Allan
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cancer; Cervical cancer; Cohort Studies; Costa Rica - epidemiology; Disease Progression; DNA Probes, HPV; DNA repair; DNA Repair - genetics; DNA, Viral - isolation & purification; DNA-Binding Proteins - genetics; Exodeoxyribonucleases - genetics; Fanconi Anemia Complementation Group A Protein - genetics; Female; Fundamental and applied biological sciences. Psychology; Genes, BRCA1; Genes, BRCA2; Genetic polymorphism; Genotypes; Haplotypes; Human genetics; Human papillomavirus; Humans; Immune response; Infections; Infectious diseases; Medical genetics; Medical sciences; Microbiology; Miscellaneous; NADPH Oxidases - genetics; Papillomaviridae - isolation & purification; Papillomavirus Infections - complications; Papillomavirus Infections - epidemiology; Papillomavirus Infections - physiopathology; Polymorphism, Single Nucleotide; Tumors; Uterine Cervical Neoplasms - epidemiology; Uterine Cervical Neoplasms - genetics; Virology; Viruses; X-ray Repair Cross Complementing Protein 1
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/595563

Background. We examined host genetic factors to identify those more common in individuals whose human papillomavirus (HPV) infections were most likely to persist and progress to cervical intraepithelial neoplasia grade 3 (CIN3) and cancer. Methods. We genotyped 92 single-nucleotide polymorphisms (SNPs) from 49 candidate immune response and DNA repair genes obtained from 469 women with CIN3 or cancer, 390 women with persistent HPV infections (median duration, 25 months), and 452 random control subjects from the 10,049-woman Guanacaste Costa Rica Natural History Study. We calculated odds ratios and 95% confidence intervals (CIs) for the association of SNP and haplotypes in women with CIN3 or cancer and HPV persistence, compared with random control subjects. Results. A SNP in the Fanconi anemia complementation group A gene (FANCA) (G501S) was associated with increased risk of CIN3 or cancer. The AG and GG genotypes had a 1.3-fold (95% CI, 0.95–1.8-fold) and 1.7-fold (95% CI, 1.1–2.6-fold) increased risk for CIN3 or cancer, respectively (Ptrend=.008; referent, AA). The FANCA haplotype that included G501S also conferred increased risk of CIN3 or cancer, as did a different haplotype that included 2 other FANCA SNPs (G809A and T266A). A SNP in the innate immune gene IRF3 (S427T) was associated with increased risk for HPV persistence (Ptrend=.009). Conclusions. Our results require replication but support the role of FANCA variants in cervical cancer susceptibility and of IRF3 in HPV persistence.