Blood group B alleles associated with increased MIS-C risk in Italian children cohort study

Multisystem 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. Eighteen 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). Blood 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. These 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.