Persistent infection with human papillomavirus (HPV) causes essentially pre-cancerous and cancer lesions in both men and women and also likely influences HPV transmission within sexual partners and thus is an important "intermediate phenotype." To date, most efforts in etiological research of HPV have focused in women. Given that men are important in transmitting HPV to their female sexual partners along with the public health burden of genital warts and several cancers, understanding the natural history of HPV in men would benefit both men and women. The purpose of this study is to test the hypothesis that differences in host genes influence HPV persistence in men. Although the mechanism for HPV persistence is unknown, several studies implicate immune evasion, involving genetically mediated determinants of the host immune response. Genetic influences of HPV in women have been reported and we propose test this hypothesis in the context of men. Our collaborative team with investigators from UAB and Moffitt Cancer Center and Research Institute has the experience and expertise that provides a unique opportunity to evaluate the genetic effects with well- documented HPV infection outcomes in men. For this new investigation, we will draw upon data from 500 Caucasian men nested within the HPV infection in Men (HIM), the only multi-national prospective study of men, which consists of 4299 participants, 18-70 years residing in southern Florida, USA, Sao Paulo, Brazil and Cuernavaca, Mexico. We will identify 250 individuals who cleared HPV16 within 6 months after acquisition and another set of 250 individuals in whom HPV16 has persisted for over 12 months and perform genotyping of variants in immune-related genes using the ImmunoChip ((~200,000 SNPs compiled from association studies of infectious and autoimmune diseases). We will perform a logistic regression type of genetic models to examine differential distribution of the genetic polymorphisms in the two groups, accounting for correlations of multiple co-infections with each HPV type as an individual outcome.
Three specific aims of the study are: 1) Extract genomic DNA from archived whole blood collected at the enrollment visit among 250 men with persistent (e 12 months) genital HPV 16 infection and 250 with transient (1x detection only) genital HPV 16;2) Genotype all 500 samples using the ImmunoChip array;and 3) Conduct statistical analyses to identify genetic variants associated with genital HPV 16 DNA clearance and persistence To our knowledge, this would be the first immunogenetic study of HPV infection outcome among men, to date. Any informative data from this study would fill in the gap of immunological effects with HPV pathogenesis in men and may help identify molecular signatures amenable to specific therapeutic approaches in men and their partners.
Our proposed immunogenetic study examining variants in immune-related genes will help explain the differential HPV infection and persistence/clearance outcomes, the intermediate phenotype necessary for cancer, in men. The findings from this research will advance our understanding of HPV infection and pathogenesis in men and judiciously allow individualized care, management and intervention of HPV infection outcome including genital cancer, according to their genetic makeup.