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HPV infrequently persists and progresses to cervical cancer. We examined host genetic factors hypothesized to play a role in determining which subset of individuals infected with oncogenic human papillomavirus (HPV) have persistent infection and further develop cervical pre-cancer/cancer compared to the majority of infected individuals who will clear infection.  We evaluated 7140 tag single nucleotide polymorphisms (SNPs) from 305 candidate genes hypothesized to be involved in DNA repair, viral infection and cell entry in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 HPV persistent women (median: 25 months), and 425 random controls (RC) from the 10,049 women Guanacaste Costa Rica Natural History study. We used logistic regression to compute odds ratios and p-trend for CIN3/cancer and HPV persistence in relation to SNP genotypes and haplotypes (adjusted for age). We obtained pathway and gene-level summary of associations by computing the adaptive combination of p-values. Genes/regions statistically significantly associated with CIN3/cancer included the viral infection and cell entry genes 2′,5′ oligoadenylate synthetase gene 3 ( OAS3 ), sulfatase 1 ( SULF1 ), and interferon gamma ( IFNG ); the DNA repair genes deoxyuridine triphosphate ( DUT ), dosage suppressor of mck 1 homolog ( DMC1 ), and general transcription factor IIH, polypeptide 3 ( GTF2H4 ); and the  EVER1  and  EVER2  genes (p<0.01). From each region, the single most significant SNPs associated with CIN3/cancer were  OAS3  rs12302655,  SULF1  rs4737999,  IFNG  rs11177074,  DUT  rs3784621,  DMC1  rs5757133,  GTF2H4  rs2894054,  EVER1/EVER2  rs9893818 (p-trends≤0.001). SNPs for  OAS3 ,  SULF1 ,  DUT , and  GTF2H4  were associated with HPV persistence whereas  IFNG  and  EVER1/EVER2  SNPs were associated with progression to CIN3/cancer. We note that the associations observed were less than two-fold. We identified variations DNA repair and viral binding and cell entry genes associated with CIN3/cancer. Our results require replication but suggest that different genes may be responsible for modulating risk in the two critical transition steps important for cervical carcinogenesis: HPV persistence and disease progression.

Common Genetic Variants and Risk for HPV Persistence and Progression to Cervical Cancer