Comprehensive genotyping of the FCGR2/3 locus reveals a novel association of FCGR2C- ORF with susceptibility to Kawasaki Disease as well as extensive ethnic variation and linkage disequilibrium

Kawasaki Disease (KD) is an acute systemic vasculitis in children. The strongest genetic association with KD found in genome-wide association studies (GWAS), is FCGR2A-H131R (rs1801274). Rs1801274 is located at the FCGR2/3 locus, which contains five highly homologous genes encoding the major receptors for IgG (Fc-gamma receptors, FcγRs). Multiple SNPs and copy number variations (CNVs) at this locus, that are not included in the GWAS, have been associated with susceptibility to various infectious and autoimmune diseases or efficacy of immunotherapy. Because of sequence complexity of this locus, most association studies can only genotype two SNPs (rs1801274 and rs396991). In contrast, with multiplex ligation-dependent probe amplification (MLPA), we detected all eight known functionally relevant SNPs and haplotypes as well as CNV at this locus and could define extensive ethnic variation and linkage disequilibrium (LD) in >1800 healthy subjects. In a fine-mapping follow-up based on both a case-control population and a family-based linkage study involving 1028 patients with KD, we found the FCGR2C-ORF haplotype (rs759550223 and rs76277413) to be significantly associated with KD (meta-P = 0.0002). The FCGR2C-ORF haplotype leads to the expression of an extra activating FcγR, i.e. FcγRIIc. Being absent in Asian individuals, this haplotype only contributed to KD susceptibility in European subjects, independent of the previously established association with FCGR2A-H131R. Our data point to a complex role of FcγRs in KD pathology, with different associations depending on the ethnic variations and LD pattern at the FCGR2/3 locus.