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

Front Immunol. 2024 Sep 18:15:1323171. doi: 10.3389/fimmu.2024.1323171. eCollection 2024.

Abstract

Introduction: 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 (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 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 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.

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 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.

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.

Keywords: CAA; FCGR2; FCGR2Ap.His166Arg; FCGR3; IVIg; Kawasaki disease; genetics.

MeSH terms

  • Case-Control Studies
  • Child
  • Child, Preschool
  • Coronary Aneurysm* / etiology
  • Coronary Aneurysm* / genetics
  • DNA Copy Number Variations
  • Drug Resistance / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Immunoglobulins, Intravenous* / therapeutic use
  • Infant
  • Male
  • Mucocutaneous Lymph Node Syndrome* / drug therapy
  • Mucocutaneous Lymph Node Syndrome* / genetics
  • Polymorphism, Single Nucleotide*
  • Receptors, IgG* / genetics

Substances

  • Receptors, IgG
  • Immunoglobulins, Intravenous
  • FCGR2A protein, human
  • FCGR3A protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a grant from the Landsteiner Foundation for Blood Transfusion Research (LSBR 2022) awarded to SQN. In addition, the Kawasaki study is funded by the Dutch Foundation Kind and Handicap and an anonymous donor. The collection of DNA samples from the US KD Genetics Consortium was funded in part by a grant to JB from the National Institutes of Health, National Heart Blood Lung Institute R01HL140898. DB is supported by a National Health and Medical Research Council (Australia) Investigator Grant APP1175744. Research at Murdoch Children’s Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program. The sponsors had no role in the study design, analysis, or decision for publication.