Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
PLoS Genet. 2013;9(1):e1003147. doi: 10.1371/journal.pgen.1003147. Epub 2013 Jan 10.
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.
人类疱疹病毒 4 型（EBV）在全球范围内广泛存在，并与传染性单核细胞增多症以及包括伯基特淋巴瘤、霍奇金淋巴瘤、鼻咽部淋巴瘤和淋巴组织增生性疾病在内的严重疾病相关。尽管 EBV 已经成为广泛研究的焦点，但对于哪些因素使一些个体更容易受到感染以及因感染而导致不良后果，仍有许多未知之处。在这里，我们使用整合基因组学方法，以便定位影响 EB 病毒核抗原-1（EBNA-1）IgG 抗体水平的遗传因素，作为感染这种病原体的历史的衡量标准，在大型墨西哥裔美国家庭中进行研究。在人类白细胞抗原（HLA）区域的染色体 6 上获得了基因组范围的连锁和关联的显著证据，并在一个独立的墨西哥裔美国家庭大样本中得到了复制（在两个数据集的综合分析中，最小的联合分析 p 值为 rs477515 和 rs2516049 的 1.4×10(-15)）。条件关联分析表明，MHC 类 II 内至少存在两个独立的基因座，并且与淋巴细胞表达数据一起表明 HLA-DRB1 和 HLA-DQB1 基因是最佳候选基因。关联信号是特异性针对 EBV 的，并且在 12 种其他被检查的病原体的 IgG 抗体中未发现，因此不仅仅揭示了一般的 HLA 效应。我们研究了与 EBV 已知或疑似发挥作用的疾病（即鼻咽部淋巴瘤、霍奇金淋巴瘤、系统性红斑狼疮和多发性硬化症）显著相关的 SNPs 是否也显示出与 EBNA-1 抗体水平相关的证据，仅发现 HLA 基因座存在重叠，但在基因组的其他部位均未发现。这项工作的意义在于，已经确定了一个与 EBV 感染相关的主要基因座，这最终可能揭示免疫系统调节这种病原体感染的潜在机制。
