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

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.

研究背景：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）后罕见的迟发性并发症，其具体病因尚未明确。本研究旨在探究新冠病毒感染（COVID-19）的遗传易感性与炎症反应失调在意大利儿童MIS-C发病过程中的作用。
研究方法：本研究共纳入18名受试者，其中12名符合典型MIS-C诊断标准，6名患有川崎病-新冠病毒相关疾病（KD，即川崎病）。研究对比了患者组、未合并MIS-C的新冠感染儿童组（n=79）以及成年对照组（n=2848）中，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，ABO tagging SNPs）以及与新冠重症相关的5个全基因组关联分析优先定位位点（GWAS-prioritized loci）的频率分布。本研究对MIS-C队列受试者进行了全外显子组测序（Whole exome sequencing, WES），以检测207个免疫相关基因组合中罕见有害变异的发生频率，并与本地对照人群（n=266）进行比较。
研究结果：血型B等位基因可独立于性别、种族、新冠感染状态以及A型血因素，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亚型的影响更为显著（OR=6.8；95%CI=1.7~35.1；p=0.007）。本研究在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；所有患者均携带至少1个此类变异。
研究结论：本研究结果不仅证实B型血可作为新冠感染儿童发生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发病基础提供了科学佐证。