Epstein–Barr virus (EBV) infects ≈90-95% of the global population1,2 and persists in B cells as a life-long infection3. Prior EBV-infection is associated with autoimmune and neoplastic disease4. Still, the biological basis of host control during EBV persistence remains unclear. Here, we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence (GS) data from 486,315 UK Biobank and 336,123 All of Us participants, we identified short read-pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV-read detection (EBVread+) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug intake, and current smoking. Genome-wide analyses of EBVread+ identified strong associations at the Major Histocompatibility Complex (MHC), including 54 independent HLA-alleles of MHC class I and II, and at 27 genomic regions outside MHC. Epistasis with distinct HLA-alleles of MHC class I was observed at the ERAP2 locus. Analysis of individuals with EBV-associated diseases4 revealed a higher polygenic burden of EBVread+ for HLA-alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01), and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread+ with inflammatory bowel disease, hypothyroidism, and type 1 diabetes. Our study establishes by-products of human GS as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.
EB病毒（EBV）感染全球约90-95%的人口1,2，并在B细胞中建立终身潜伏感染3。既往EBV感染与自身免疫性疾病和肿瘤性疾病相关4。然而，EBV潜伏感染期间宿主控制的生物学基础仍不清楚。在此，我们报告了与持续感染期间EBV控制相关的非遗传因素和遗传因素的鉴定。利用来自英国生物银行486,315名参与者和“All of Us”研究项目336,123名参与者的血液基因组测序数据，我们分别在16.2%和21.8%的个体中鉴定出映射到EBV基因组的短读段对。EBV读段检测阳性反映了血细胞中病毒载量的增加（通过正交测量验证），并与HIV感染、免疫抑制药物摄入以及当前吸烟相关。针对EBV读段检测阳性的全基因组分析发现了主要组织相容性复合体区域的强关联，包括54个独立的MHC I类和II类HLA等位基因，以及MHC区域外的27个基因组区域。在ERAP2基因座观察到与特定MHC I类HLA等位基因的上位效应。对EBV相关疾病患者4的分析显示，在多发性硬化症中，MHC I类HLA等位基因（由HLA-A*02:01驱动）的EBV读段检测阳性多基因负担更高；在类风湿关节炎中，MHC II类等位基因的负担更高。全表型组分析发现EBV读段检测阳性与炎症性肠病、甲状腺功能减退和1型糖尿病存在多基因重叠。我们的研究确立了人类基因组测序的副产物作为EBV病毒载量的替代标志物，这将促进EBV及其他持续性病毒感染的研究与治疗。
肿瘤(癌症)患者之家