Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Front Immunol. 2020 Jan 24;11:14. doi: 10.3389/fimmu.2020.00014. eCollection 2020.
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 W01:01:01-DMA01:01:01-DMB01:03:01:02-TAP101:01:01 ( < 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.
在大多数普通可变免疫缺陷症（CVID）患者中，其发病机制仍然未知，CVID 是最常见的有症状原发性免疫缺陷症。我们旨在比较单基因 CVID 患者与未检测到已知遗传突变的患者之间的次要和主要组织相容性复合体（MHC）标志物以及常见遗传变异的多基因评分。通过全外显子组测序在 CVID 队列中识别单基因患者。进行了计算全分辨率 MHC 分型和基于确认性 PCR 扩增子的高分辨率分型。使用显著不同的变体开发了外显子范围多基因评分，并使用多变量孟德尔随机化（MR）分析来测试抗体水平和易感性的显著遗传变异的因果关系。在 83 名 CVID 患者（44.5%为女性）中，发现 40 名个体存在单基因缺陷。对未检测到已知遗传突变的其余 CVID 患者进行评估显示，分别有 13 个和 27 个 MHC Ⅰ类和Ⅱ类等位基因显著相关。与未解决的 CVID 最显著的部分单倍型相关联的是 W01:01:01-DMA01:01:01-DMB01:03:01:02-TAP101:01:01（<0.001），其携带者疾病发病较晚，只有感染的临床表现，为非家族性 CVID，生发中心后缺陷和疾病呈非进行性形式。排除单基因疾病后，MR 分析可识别与细菌感染相关的显著遗传变异，并改善了以前与低多效性的 GWAS 研究中观察到的 MR 分析的差异，主要是针对下呼吸道感染、细菌感染和链球菌感染。这是第一项关于 CVID 患者的次要和主要 MHC 分型和多基因评分的全分辨率研究，表明排除疾病的单基因形式揭示了 MHC 基因和常见遗传变异在 CVID 发病机制中的独立作用。
