Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.

中文翻译：

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EB 病毒免疫反应的遗传学：多发性硬化症发病机制的前景

EB 病毒 (EBV) 感染被认为是发生多发性硬化症 (MS) 以及可能传播该疾病的先决条件。然而，这种影响的确切机制仍不清楚。一项大规模研究调查 EBV 血清学和相关临床表现（例如传染性单核细胞增多症 (IM)）的宿主遗传学，可能有助于我们更好地了解 EBV 在 MS 发病机制中的作用。本研究评估了影响 EBV 血清学反应和 IM 病史的宿主遗传因素，并将其与瑞典人群的 MS 风险和遗传易感性进行交叉评估。使用基于微珠的多重血清学方法测量针对 EBV 核抗原 1（EBNA-1，截短=aa[325-641]，肽=aa[385-420]）和病毒衣壳抗原 p18 (VCAp18) 的血浆 IgG 抗体水平，以检测8744 例 MS 病例和 7229 例人群匹配对照。将高/低 EBV 抗体水平和 IM 病史的 MS 风险关联与相关临床指标以及性别、采样年龄和相关 HLA 等位基因变异进行比较。还进行了全基因组和 HLA 等位基因关联分析，以确定 EBV 抗体反应和 IM 病史的遗传风险因素。针对 VCAp18（OR=1.74，95% CI=1.60-1.88）和 EBNA-1，尤其是肽（OR=3.13，95% CI=2.93-3.35）的较高抗体水平与 MS 风险增加相关。随着抗 EBNA-1 IgG 水平升高，风险增加，最高可达参考风险的 12 倍。我们还鉴定了几种与 EBV 血清学相关的独立 HLA 单倍型，与已知的 MS 风险等位基因重叠（例如 DRB1*15:01）。尽管有多个候选者，但 HLA 区域之外的变异没有达到全基因组意义。抗 EBNA-1 IgG 水平（尤其是肽片段）的累积 HLA 风险与 MS 密切相关。相比之下，高抗 VCAp18 IgG 水平的遗传风险与 MS 风险的相关性并不那么强。 IM病史与II类HLA基因无关，但与A*02:01负相关，A*02:01对MS有保护作用。我们的研究结果强调，抗 EBNA-1 IgG 水平与 MS 之间的风险关联可能部分归因于 HLA 关联的重叠。此外，随着抗 EBNA-1 水平的增加，MS 风险也随之增加，这可能与 EBNA-1 免疫反应的致病作用一致，这可能是通过分子模拟实现的。鉴于高抗 EBNA-1 抗体可能反映出 T 细胞对病毒的防御控制不佳，我们的研究结果与 DRB1*15:01 在针对 EBV 的免疫防御中是较差的 II 类抗原是一致的。最后，IM 遗传控制的差异支持 EBNA-1 和 IM 在 MS 易感性中的独立作用。