A Genome-Wide Integrative Genomic Study Localizes Genetic Factors Influencing Antibodies against Epstein-Barr Virus Nuclear Antigen 1 (EBNA-1)

Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
PLoS Genetics (Impact Factor: 7.53). 01/2013; 9(1):e1003147. DOI: 10.1371/journal.pgen.1003147
Source: PubMed


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.

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Available from: Rohina Rubicz
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    • "In both studies, the minor allele was associated with lower anti-EBNA-1 IgG levels. The other SNPs reported in the previous study [3] were not significantly associated with anti-EBNA-1 IgG levels in our sample. The previous study was conducted in Mexican American subjects, and allele frequencies and LD patterns differ between the MEX and CEU HapMap populations (Table S1), potentially accounting, at least in part, for the observed difference between the two studies. "
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    Full-text · Article · Jul 2014 · PLoS ONE
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    • "underwent stringent quality control measures prior to analysis, as previously described [Rubicz et al., 2013]. SNPs were excluded if they had a low call rate, were monomorphic, had a minor allele in <10 individuals, and if Hardy-Weinberg test statistics (calculated in SOLAR [Almasy and Blangero, 1998]) were P ࣘ 10 –4 . "
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