AUTHOR=Uittenbogaard Paula , Netea Stejara A. , Tanck Michael W. T. , Geissler Judy , Buda Piotr , Kowalczyk-Domagała Monika , Okarska-Napierała Magdalena , van Stijn Diana , Tacke Carline E. ,  US Kawasaki Disease Genetics Consortium , Burgner David P. , Shimizu Chisato , Burns Jane C. , Kuipers Irene M. , Kuijpers Taco W. , Nagelkerke Sietse Q. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1323171

DOI=10.3389/fimmu.2024.1323171

ISSN=1664-3224

ABSTRACT=Introduction: Kawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases CAA risk, possibly through competitive binding to Fc-gamma Receptors (Fc𝛾Rs), reducing the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased CAA risk. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance or CAAs. Methods: We 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, CAA risk) in different cohorts adding up to 1,167 KD cases in total. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search. Results: FCGR2A-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 nor 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. Discussion: FCGR2/3 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.