High-risk mucosal types of human papillomavirus (HPV) cause anogenital and oropharyngeal cancers, whereas cutaneous types (e.g. HPV8 and 77) are suspected to be involved in non-melanoma skin cancer. The antibody response to HPVs is a key determinant of protective immunity, but not all infected individuals seroconvert. Genetic variability of the host may have large impact on seroconversion. A previous genome-wide association study (GWAS) has identified a susceptibility locus (rs41270488) for HPV8 seropositivity within the major histocompatibility complex (MHC) region. To further study this locus, we imputed alleles at classical leukocyte antigen (HLA) loci using HLA*IMP:02 with a reference panel from the HapMap Project and the 1958 Birth Cohort, and conducted an integrated analysis among 4811 central European subjects to assess the contribution of classical HLA alleles and gene copy number variation (CNV) at the hypervariable DRB locus within the MHC region to HPV seropositivity at both the individual HPV type level and the phylogenetic species level. Our study provides evidence that the association noted between rs41270488 and HPV8 seropositivity is driven by two independent variants, namely DQB1*0301 [odds ratio (OR) = 1.51, 95% confidence interval (CI) = 1.36-1.68, P = 1.0 × 10(-14)] and DRB1*1101 (OR = 1.89, 95%CI = 1.57-2.28, P = 1.5 × 10(-11)) within the HLA class II region. Additionally, we identified two correlated alleles DRB1*0701 (OR = 1.67, 95%CI = 1.41-1.98, P = 2.6 × 10(-9)) and DQA1*0201 (OR = 1.67, 95%CI = 1.38-1.93, P = 1.7 × 10(-8)), to be associated with HPV77 seropositivity. Comparable results were observed through imputation using SNP2HLA with another reference panel from the Type 1 diabetes Genetics Consortium. This study provides support for an important role of HLA class II alleles in antibody response to HPV infection.

Centre D'innovation Génome Québec et Université McGill Montréal Canada

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Cancer Epidemiology and Prevention M Sklodowska Curie Memorial Cancer Center and Institute of Oncology Warsaw Poland

Department of Epidemiology Institute of Occupational Medicine Lodz Poland

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala Uppsala University Uppsala Sweden

Department of Neurosurgery 1st Affiliated Hospital of Nanjing Medical University Nanjing China

Department of Neurosurgery Huashan Hospital Shanghai Medical School Fudan University Shanghai China

Genetic Cancer Susceptibility Group International Agency for Research on Cancer Lyon France

Genetic Epidemiology Group

Infections and Cancer Epidemiology Group Division of Genome Modifications and Carcinogenesis

Institute of Carcinogenesis Cancer Research Centre Moscow Russia

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala Uppsala University Uppsala Sweden

Mount Sinai Hospital Icahn Medical Institute New York USA and

National Institute of Environmental Health Budapest Hungary

Palacky University Olomouc Czech Republic

Regional Authority of Public Health Banská Bystrica Slovakia

St Mary General and Esophageal Surgery Clinic Carol Davila University of Medicine and Pharmacy Bucharest Romania

Virus Host Interactions of Polyoma and Papilloma Viruses Group Division of Genome Modifications and Carcinogenesis German Cancer Research Center Heidelberg Germany