Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p -value in combined analysis of both datasets is 1.4×10 −15 for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen. Author Summary Many factors influence individual differences in susceptibility to infectious disease, including genetic factors of the host. Here we use several genome-wide investigative tools (linkage, association, joint linkage and association, and the analysis of gene expression data) to search for host genetic factors influencing Epstein-Barr virus (EBV) infection. EBV is a human herpes virus that infects up to 90% of adults worldwide, infection with which has been associated with severe complications including malignancies and autoimmune disorders. In a sample of >1,300 Mexican American family members, we found significant evidence of association of anti–EBV antibody levels with loci on chromosome 6 in the human leukocyte antigen region, which contains genes related to immune function. The top two independent loci in this region were HLA-DRB1 and HLA-DQB1 , both of which are involved in the presentation of foreign antigens to T cells. This finding was specific to EBV and not to 12 other pathogens we examined. We also report an overlap of genetic factors influencing both EBV antibody level and EBV–related cancers and autoimmune disorders. This work demonstrates the presence of EBV susceptibility loci and provides impetus for further investigation to better understand the underlying mechanisms related to differences in disease progression among individuals infected with this pathogen.
【초록키워드】 Adult, Gene Expression, multiple sclerosis, antibody, T cells, susceptibility, Cancer, Genome, Genetic, SNPs, Infection, human leukocyte antigen, systemic lupus erythematosus, Infectious disease, immune system, virus, adverse outcomes, Antigen, adverse outcome, Disease progression, Gene, lymphocyte, IgG antibody, pathogen, IgG antibodies, cancers, Research, Epstein-Barr virus, SNP, immune function, Pathogens, MHC class II, dataset, antibody levels, HLA, infectious, disease, mechanism, EBV, association, Evidence, linkage, Analysis, regulate, Autoimmune disorders, severe disease, malignancy, lupus erythematosus, a major, genetic factors, evidence of, best, Hodgkin lymphoma, nasopharyngeal lymphoma, Burkitt lymphoma, family members, focus, leukocyte, Candidates, Factor, infectious mononucleosis, lymphoproliferative disorders, locus, chromosome, chromosome 6, overlap, Author, individual, P -value, measure, malignancies, expression data, DRB1, severe complications, loci, DQB1, HLA-DQB1, HLA-DRB1, susceptibility loci, Epstein Barr virus, foreign antigens, HLA locus, nuclear, MHC class, infect, Host, approach, Infected, independent, prevalent, joint, found, related, examined, significantly, involved, investigated, provide, not found, replicated, concerning, was obtained, foreign antigen, severe complication, 【제목키워드】 genetic factors,