title: A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1).
abstract: 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.
authors: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America. rohina@TxBiomedGenetics.org
authors: Rohina
authors: R
authors: Rubicz
authors: Robert
authors: R
authors: Yolken
authors: Eugene
authors: E
authors: Drigalenko
authors: Melanie A
authors: MA
authors: Carless
authors: Thomas D
authors: TD
authors: Dyer
authors: Lara
authors: L
authors: Bauman
authors: Phillip E
authors: PE
authors: Melton
authors: Jack W
authors: JW
authors: Kent
authors: John B
authors: JB
authors: Harley
authors: Joanne E
authors: JE
authors: Curran
authors: Matthew P
authors: MP
authors: Johnson
authors: Shelley A
authors: SA
authors: Cole
authors: Laura
authors: L
authors: Almasy
authors: Eric K
authors: EK
authors: Moses
authors: Nikhil V
authors: NV
authors: Dhurandhar
authors: Ellen
authors: E
authors: Kraig
authors: John
authors: J
authors: Blangero
authors: Charles T
authors: CT
authors: Leach
authors: Harald H H
authors: HH
authors: Göring
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000097:blood / Q000235:genetics*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000097:blood*; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity; D006689:Hodgkin Disease / Q000235:genetics / Q000821:virology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000821:virology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000821:virology; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000821:virology; D020641:Polymorphism, Single Nucleotide
chemical_list: D000906:Antibodies; D019309:Epstein-Barr Virus Nuclear Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D007074:Immunoglobulin G; C417029:EBV-encoded nuclear antigen 1