Contents lists available at ScienceDirect Papillomavirus Research journal homepage: www.elsevier.com/locate/pvr Variants in immune-related genes and genital HPV 16 persistence in men Bigyan Mainali a , Matthew B. Schabath b , Staci L. Sudenga b,c , Yuanfan Ye a , Howard W. Wiener a , Luisa L. Villa d , Anna R. Giuliano b , Sadeep Shrestha a, ⁎ a Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35242, USA b Center for Infection Research in Cancer, Moffitt Caner Center, Tampa, FL, USA c Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA d School of Medicine, Universidade de São Paulo, São Paulo, Brazil ARTICLE INFO Keywords: HPV in men HPV persistence Immunogenetics ABSTRACT Objectives: While most human papillomavirus (HPV) infection clears on its own, persistent HPV infection can cause genital warts and anal, penile and oropharyngeal cancers in men. We conducted genetic analysis in a sub- cohort of the HPV infection in men (HIM) study to test the hypothesis that differences in host genes influence HPV persistence in men. Methods: Baseline and longitudinal genital HPV status at the genitals was measured every 6-months using the Linear Array assay amplified HPV L1 gene fragment using the PGMY09/11 L1 consensus primer system. DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) in the customized genome- wide genotyping array, the “TxArray,” were examined using logistic regression in a case-control study design to assess the association with HPV16 persistence/clearance. Results: Of the total of 737,742 autosomal SNPs in the array, 605,885 passed basic quality control and were examined between 40 men (cases) with > 18 months persistent genital HPV 16 infection vs. 151 controls who were HPV 16-positive, but whose infections cleared in < 18 months. The logistic regression analysis from this case-control study showed variants in several gene regions associated with genital HPV 16 persistence, with the strongest association detected with SNPs on chromosomes 20 (p < 5.72 × 10 -6 ) and 15 (p < 5.89 × 10 -6 ), after adjusting for age, smoking status, number of sex partners and four principal components (ancestral background). Conclusions: Our results provide a preliminary basis for understanding the biological mechanism of oncogenic HPV 16 pathogenesis at the genitals in men. Some of the genes flanking the top hit SNPs are consistent with previous findings in both HPV related and non-related cancers but further genetic studies in larger cohorts are warranted to confirm these and identify novel major susceptibility genes involved in the pathogenesis of genital HPV persistence in men. 1. Background Human Papilloma Virus (HPV) is the most common sexually trans- mitted infection (STIs) in both men and women worldwide, including the United States (US) [1]. In men, the HPV genotypes that are most frequently detected in genital warts are HPV 6 and 11 (96–100%), and HPV 16 is the predominant type detected in penile cancer [2]. While penile cancer is considered a rare cancer with 22,000 estimated cases per year worldwide, it is still associated with high morbidity and mortality [2]. Some cohort studies reveal that anogenital HPV incidence is at least as high among men as it is in women [3]. Duration of HPV infections is also comparable between men and women with HPV 16 infections having a longer duration than most other high-risk HPV types in both men and women [4]. However, unlike women where HPV incidence decreases with older age, men remain susceptible to incident HPV in- fections across their lifespan [5]. Men are also less likely to naturally acquire HPV antibodies compared to women, regardless of the popu- lation studied [4]. It is unknown if the systemic immune response to HPV in men is similar to that in women. The majority of HPV infection clears spontaneously, whereas in a subset it persist [1,6], defined as intermediate phenotype, leading to cervical cancer [6]. However, the natural history of HPV-associated penile cancer, including differential HPV persistence is not fully known in men, but similar process as in https://doi.org/10.1016/j.pvr.2018.08.001 Received 9 June 2018; Received in revised form 31 July 2018; Accepted 1 August 2018 ⁎ Corresponding author. E-mail address: sshrestha@uab.edu (S. Shrestha). Papillomavirus Research 7 (2019) 11–14 Available online 06 August 2018 2405-8521/ © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). T