title: A systematic investigation of the contribution of genetic variation within the MHC region to HPV seropositivity.
abstract: 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.
authors.affiliation: 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, simpledandan1981@163.com dan.chen@igp.uu.se brennanp@iarc.fr.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Genetic Epidemiology Group.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gaborieau
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Chabrier
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Infections and Cancer Epidemiology Group, Division of Genome Modifications and Carcinogenesis.
authors.forename: Tim
authors.initials: T
authors.lastname: Waterboer
authors.affiliation: Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia.
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.affiliation: Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.affiliation: National Institute of Environmental Health, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Rudnai
authors.affiliation: Regional Authority of Public Health, Banská Bystrica, Slovakia.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fabianova
authors.affiliation: Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.affiliation: Palacky University, Olomouc, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.affiliation: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.affiliation: St Mary General and Esophageal Surgery Clinic, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Ioan Nicolae
authors.initials: IN
authors.lastname: Mates
authors.affiliation: Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland.
authors.forename: Neonila
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.affiliation: Mount Sinai Hospital, Icahn Medical Institute, New York, USA and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.affiliation: Virus-Host Interactions of Polyoma and Papilloma Viruses Group, Division of Genome Modifications and Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: Centre D'innovation Génome Québec et Université McGill, Montréal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: Genetic Epidemiology Group, simpledandan1981@163.com dan.chen@igp.uu.se brennanp@iarc.fr.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D027383:Papillomaviridae / Q000145:classification / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D020641:Polymorphism, Single Nucleotide
chemical_list: D006680:HLA Antigens