Extensive Ethnic Variation and Linkage Disequilibrium at the Locus: Different Genetic Associations Revealed in Kawasaki Disease.

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the -ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the -ORF haplotype showed strong LD with, among others, rs201218628 (-Q27W, = 0.63). LD between these two variants was weaker ( = 0.17) in Africans, whereas the -ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The -ORF haplotype and rs1801274 (-H131R) were in weak LD ( = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the -ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the locus with knowledge of LD and ethnic variation.