Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses.
Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses.
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DOI：
10.1016/j.ajhg.2015.09.008
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发表时间：
2015-11-05
影响因子：
9.8
通讯作者：
Fellay J
中科院分区：
文献类型：
--
作者：
Hammer C;Begemann M;McLaren PJ;Bartha I;Michel A;Klose B;Schmitt C;Waterboer T;Pawlita M;Schulz TF;Ehrenreich H;Fellay J
人抗体对病毒抗原的反应程度是高度可变的。为了探索人类遗传对这种变异性的贡献，我们在2，363名免疫功能正常的成年人中进行了免疫球蛋白G对14种病原性病毒反应的全基因组关联研究。在6号染色体上的主要组织相容性复合体区域观察到甲型流感病毒、EB病毒、JC多瘤病毒和默克尔细胞多瘤病毒的显著相关性。使用本地插补和精细映射，我们确定了人类白细胞抗原（HLA）II类蛋白的特定氨基酸残基作为这些关联信号的最可能的因果变异。常见的HLA-DR β 1单倍型显示出病毒特异性的体液反应调节模式。我们观察到影响对甲型流感和EBV的体液应答的变异体与先前与这些病毒相关的自身免疫性疾病相关的变异体之间存在重叠。这项研究的结果强调了中央和病原体特异性的作用，HLA II类变异的调制体液免疫反应的病毒抗原在人类。
The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.