TY - JOUR
T1 - A systematic investigation of the contribution of genetic variation within the MHC region to HPV seropositivity
AU - Chen, Dan
AU - Gaborieau, Valérie
AU - Zhao, Yao
AU - Chabrier, Amélie
AU - Wang, Huibo
AU - Waterboer, Tim
AU - Zaridze, David
AU - Lissowska, Jolanta
AU - Rudnai, Peter
AU - Fabianova, Eleonora
AU - Bencko, Vladimir
AU - Janout, Vladimir
AU - Foretova, Lenka
AU - Mates, Ioan Nicolae
AU - Szeszenia-Dabrowska, Neonila
AU - Boffetta, Paolo
AU - Pawlita, Michael
AU - Lathrop, Mark
AU - Gyllensten, Ulf
AU - Brennan, Paul
AU - McKay, James D.
N1 - Publisher Copyright:
© The Author 2015.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84936888583
U2 - 10.1093/hmg/ddv015
DO - 10.1093/hmg/ddv015
M3 - Article
C2 - 25616963
AN - SCOPUS:84936888583
SN - 0964-6906
VL - 24
SP - 2681
EP - 2688
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 9
ER -