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=15

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=<sec><title>Introduction</title><p>Kawasaki 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 (Fc<italic>γ</italic>Rs), 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 <italic>FCGR2/3</italic> locus associated with susceptibility to KD, IVIg resistance, or CAA.</p></sec><sec><title>Materials and methods</title><p>We investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the <italic>FCGR2/3</italic> 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.</p></sec><sec><title>Results</title><p><italic>FCGR2A-</italic>p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, <italic>p</italic> = 0.0015). In case–control analyses, all of the investigated genetic variations at the <italic>FCGR2/3</italic> locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the <italic>FCGR3B-</italic>NA2 haplotype (OR = 2.15, 95% CI = 1.15–4.01, <italic>p</italic> = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the <italic>FCGR2/3</italic> locus with IVIg resistance or CAA risk.</p></sec><sec><title>Discussion</title><p><bold>FCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation.</bold> Currently known genetic variations at the <italic>FCGR2/3</italic> locus are not useful in prediction models for IVIg resistance or CAA risk.</p></sec>