Extensive Ethnic Variation and Linkage Disequilibrium at the FCGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease.

Sietse Q Nagelkerke,Martin L Hibberd,Martin De Boer,Judy Geissler,Eileen Png,C Ellen Van Der Schoot,Timo K Van Den Berg,Willemijn B Breunis,Karin Fijnvandraat,Justine A Ellis,Chisato Shimizu,Taco W Kuijpers,Rolando Cimaz,Rae S M Yeung,Jane C Burns,Victoria J Wright,Carline E Tacke,David Burgner ,Ahmad Nazri Mohamed Naim ,Sonia Dávila ,Long Hoàng ,Jeroen Van Der Heijden ,Michael W.t Tanck ,Michael Levin ,Anne‐Louise Ponsonby

doi:10.3389/fimmu.2019.00185

Abstract

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 FCGR2/3 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 FCGR2/3 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 FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r2 = 0.63). LD between these two variants was weaker (r2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C-ORF haplotype and rs1801274 (FCGR2A-H131R) were in weak LD (r2 = 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 FCGR2C-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 FCGR2/3 locus with knowledge of LD and ethnic variation.

Highlights

The human cellular receptors for Immunoglobulin G (IgG), the Fc-gamma receptors (FcγR), have an important role in immunity by linking the adaptive and innate immune systems
Allele Frequencies of copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) at the FCGR2/3 Locus Vary Among Different Ethnic Groups, Especially for the Classic and Nonclassic FCGR2C-ORF Allele frequency (ORF) Haplotypes
Significant differences (P < 0.05) between ethnic groups were found for CNV regions (CNRs) and for all SNPs except the FCGR3A-V158F SNP, which had no difference in frequency among all groups (Table 1)

Summary

Introduction

The human cellular receptors for Immunoglobulin G (IgG), the Fc-gamma receptors (FcγR), have an important role in immunity by linking the adaptive and innate immune systems. In the present study, including more than 4,000 individuals, we found marked ethnic differences in allele frequencies for most of the SNPs and CNVs. The most prominent difference was observed for the FCGR2C-ORF haplotype, which we have previously shown to result in expression of the activating FcγRIIc [35].

Results

Conclusion