The pathogenesis in the majority of patients with common variable immunodeficiency (CVID), the most common symptomatic primary immunodeficiency, remains unknown. We aimed to compare the minor and major histocompatibility complex (MHC) markers as well as polygenic scores of common genetic variants between patients with monogenic CVID and without known genetic mutation detected. Monogenic patients were identified in a CVID cohort using whole exome sequencing. Computational full-resolution MHC typing and confirmatory PCR amplicon-based high-resolution typing were performed. Exome-wide polygenic scores were developed using significantly different variants and multi-variant Mendelian randomization (MR) analyses were used to test the causality of significant genetic variants on antibody levels and susceptibility to infectious diseases. Among 83 CVID patients (44.5% females), monogenic defects were found in 40 individuals. Evaluation of the remaining CVID patients without known genetic mutation detected showed 13 and 27 significantly associated MHC-class I and II alleles, respectively. The most significant partial haplotype linked with the unsolved CVID was W*01:01:01-DMA*01:01:01-DMB*01:03:01:02-TAP1*01:01:01 (P < 0.001), where carriers had a late onset of the disease, only infection clinical phenotype, a non-familial form of CVID, post-germinal center defects and a non-progressive form of their disease. Exclusion of monogenic diseases allowed MR analyses to identify significant genetic variants associated with bacterial infections and improved discrepancies observed in MR analyses of previous GWAS studies with low pleiotropy mainly for a lower respiratory infection, bacterial infection and Streptococcal infection. This is the first study on the full-resolution of minor and major MHC typing and polygenic scores on CVID patients and showed that exclusion of monogenic forms of the disease unraveled an independent role of MHC genes and common genetic variants in the pathogenesis of CVID.

中文翻译：

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未解决抗体缺乏症的组织相容性复杂状态和孟德尔随机分析。

大多数具有共同可变免疫缺陷（CVID）（最常见的症状性原发性免疫缺陷）的患者的发病机制仍然未知。我们旨在比较单基因CVID和未检测到已知基因突变的患者之间的次要和主要组织相容性复合物（MHC）标记以及常见遗传变异的多基因评分。使用全外显子组测序在CVID队列中鉴定了单基因患者。进行了计算全分辨率MHC分型和基于确认PCR扩增子的高分辨率分型。使用显着不同的变体开发了全基因组范围的多基因评分，并使用多变量孟德尔随机化（MR）分析来测试重要遗传变体在抗体水平和对传染病敏感性方面的因果关系。在83名CVID患者（女性占44.5％）中，有40人发现了单基因缺陷。对未检测到已知基因突变的其余CVID患者的评估显示，分别有13和27个显着相关的MHC I类和II类等位基因。与未解决的CVID关联的最重要的部分单倍型是W * 01：01：01-DMA * 01：01：01-DMB * 01：03：01：02-TAP1 * 01：01：01（P <0.001），携带者发病较晚，仅感染临床表型，非家族形式的CVID，发芽后中心缺损和疾病的非进行性形式。排除单基因疾病后，MR分析就可以识别出与细菌感染相关的重要遗传变异，并改善了先前GWAS研究的MR分析中观察到的差异，这些差异主要是针对下呼吸道感染的多效性低，细菌感染和链球菌感染。这是对CVID患者的主要和主要MHC分型和多基因评分的全分辨率的第一项研究，并表明排除该疾病的单基因形式揭示了MHC基因和常见遗传变异在CVID发病机理中的独立作用。