FCGR2/3 polymorphisms are associated with susceptibility to Kawasaki disease but do not predict intravenous immunoglobulin resistance and coronary artery aneurysms

• Published in: Frontiers in Immunology
• Main Authors: Paula Uittenbogaard, Stejara A. Netea, Michael W. T. Tanck, Judy Geissler, Piotr Buda, Monika Kowalczyk-Domagała, Magdalena Okarska-Napierała, Diana van Stijn, Carline E. Tacke, US Kawasaki Disease Genetics Consortium, David P. Burgner, Chisato Shimizu, Jane C. Burns, Irene M. Kuipers, Taco W. Kuijpers, Sietse Q. Nagelkerke
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2024-09-01
• Subjects: Kawasaki disease; IVIg; CAA; FCGR2; FCGR3; genetics
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1323171/full

IntroductionKawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA.Materials and methodsWe investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case–control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search.ResultsFCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case–control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15–4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk.DiscussionFCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.