Data Sheet 1_Association of blood group B and of rare variants affecting immune system with multisystem inflammatory syndrome in children in an Italian cohort.pdf

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is an uncommon delayed complication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children, whose cause remains unknown. The aim of this study was to investigate the role of genetic predisposition to COVID-19 and dysregulated inflammatory response in the development of MIS-C in Italian children.
MethodsEighteen individuals were enrolled: 12 with classical MIS-C and 6 with a Kawasaki–SARS-CoV-2-related disease (KD). The frequency distribution of the main common risk variants underpinning COVID-19 susceptibility (ABO tagging SNPs) and severity (five GWAS-prioritized loci) was compared between patients and children with COVID-19 without MIS-C and with adult controls (n = 79 and n = 2,848, respectively). Whole exome sequencing (WES) was performed in the MIS-C cohort to examine the frequency of rare damaging variants in a panel of 207 immune-related genes as compared to that of local controls (n = 266).
ResultsBlood group B alleles conferred an increased risk of MIS-C independently of sex, ethnicity, the presence of COVID-19, and blood group A [odds ratio (OR) 2.9; 95% confidence interval (CI) 1.04–8.5; p = 0.04], with a larger impact on the KD subphenotype (OR 6.8; 95% CI 1.7–35.1; p = 0.007). A total of 49 rare damaging variants, 4 classified as pathogenic, were prioritized in 39 immune-related genes; all patients harbored at least one variant.
ConclusionsThese results not only support a role of blood group B as a risk factor for MIS-C development in children with COVID-19, possibly through modulation of the coagulability and microvascular dysfunction, but also support an immune-genetic basis for this condition.

背景 儿童多系统炎症综合征（Multisystem inflammatory syndrome in children, MIS-C）是儿童感染严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）后少见的迟发性并发症，其具体病因至今尚未明确。本研究旨在探究新冠病毒感染遗传易感性与失调的炎症反应在意大利儿童MIS-C发病过程中的作用。
方法 本研究共纳入18名受试者：12名符合典型MIS-C诊断标准，6名罹患川崎病（Kawasaki disease, KD）合并新冠病毒感染相关疾病。针对与新冠易感性相关的主要常见风险变异（ABO标签单核苷酸多态性，single nucleotide polymorphism, SNPs）以及与新冠重症相关的5个全基因组关联研究（Genome-Wide Association Study, GWAS）优先定位位点的频率分布，在患者组、未发生MIS-C的新冠感染儿童组与成年对照组（样本量分别为79和2848）之间进行了对比分析。此外，对MIS-C队列开展全外显子组测序（Whole Exome Sequencing, WES），对比其207个免疫相关基因的罕见有害变异频率与本地对照人群（n=266）的变异频率。
结果 血型B型等位基因可独立于性别、种族、新冠感染史及A型血型，增加MIS-C的发病风险（比值比（odds ratio, OR）=2.9；95%置信区间（confidence interval, CI）：1.04~8.5；p=0.04），且对KD亚表型的影响更为显著（OR=6.8；95%CI：1.7~35.1；p=0.007）。本研究共在39个免疫相关基因中筛选出49个罕见有害变异，其中4个被归类为致病性变异；所有受试患者均携带至少1个此类变异。
结论 本研究结果不仅证实B型血型可作为新冠感染儿童罹患MIS-C的风险因素，其潜在机制可能与调控凝血功能及微血管功能障碍有关，同时也为该疾病的免疫遗传基础提供了有力证据支持。