Genetic Ancestry and Variants Correlate with the Risk of HPV Oral Infection in Adult Healthy Men

Abstract

<h3>Purpose/Objective(s)</h3> Chronic oral infection with high-risk HPV may correlate with the risk of developing HPV+ oropharynx cancer. Gender and age are associated with infection rates but the role of ethnicity/race and country of origin are less well understood. Also there has not been genetic variant(s) identified which correlate with HPV infection risk. We tested saliva samples in healthy young adult males and used whole genomic sequencing (WGS) results to explore whether genomic ancestry and individual genetic variants correlate with HPV infection. <h3>Materials/Methods</h3> Saliva samples and WGS results were analyzed from adult males who participated in a large longitudinal health study which included subjects born in 110 different countries who now reside in the U.S. HPV DNA and serotypes were identified using nested PCR and NGS sequencing and confirmed with Sanger sequencing. WGS was done at 40X coverage. WGS results were filtered to retain calls with read depth > 8, genotype quality > 30, and allele balance between 0.25 and 0.75. Variants from all individuals were merged and biallelic SNPs were selected based on minor allele frequency > 0.05, missingness < 0.05 and p-value for Hardy-Weinberg Equilibrium > 10-6 resulting in a total of 5,370,021 SNPs. All samples were confirmed to have a call rate > 98%<i>.</i> Ancestry was estimated for each subject with Genetic Relationship and Fingerprinting (GRAF) software using genotypes from 10,000 pre-selected fingerprint SNPs which characterize 9 different genomic ancestries. <h3>Results</h3> 1,272 subjects were included. Age range was 19-55 yrs (mean 34.4). 82 subjects (6.4%) had HPV virus detected with 28 different HPV serotypes; 46 cases had high-risk HPV serotypes. Cases were older than controls (36.0 vs 34.3 yrs, p=0.01), but did not differ from controls in smoking status, BMI, or other demographic variables. Infections rates differed significantly based on genomic ancestry (p=0.003). Subjects of African and Africa-American ancestries had the highest infection rates. Hispanic and European ancestries also had high rates. No subject of East Asian or Asian Pacific Islander ancestry had detectable HPV infection. A SNP variant in 3q26 was identified which was present in cases at a higher frequency than controls (p > 10^-7). <h3>Conclusion</h3> The HPV infection rate in this diverse young adult male population was high, and differed significantly based on genomic ancestries. Genetic variability may in part explain the risk of chronic HPV infection and the development of HPV-associated oropharynx cancers.