Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.

传染源通过急性感染及其慢性后遗症对全球疾病负担做出了重大贡献。我们利用英国生物银行来识别影响对多种感染的体液免疫反应的遗传位点。通过对英国生物银行 9,611 名参与者进行的 45 项全基因组关联研究，我们发现NFKB1是与多种病原体（包括疱疹病毒、逆转录病毒和多瘤病毒家族的病原体）的定量抗体反应相关的位点。一种被认为影响NFKB1表达的插入缺失变体 (rs28362491)，被定位为可能的因果变体，并且可能在免疫反应的调节中发挥关键作用。通过使用 487,297 名英国生物银行参与者的 121 个感染和炎症相关特征，我们发现缺失等位基因与多种病原体感染的风险增加相关，但对过敏性疾病具有保护作用。我们认为，由于缺失，NFKB1的表达发生改变，调节造血途径，并可能影响细胞存活、抗体产生和炎症。综上所述，我们发现，严格调节的免疫过程的破坏可能会破坏免疫反应加剧和过敏之间的平衡，或者感染风险增加和炎症消退受损之间的平衡。