Data_Sheet_1_Extensive Ethnic Variation and Linkage Disequilibrium at the FCGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease.doc

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.

人类Fcγ受体（Fc-gamma receptors, FcγRs）通过结合免疫球蛋白G（immunoglobulin G, IgG）连接适应性免疫与先天免疫。所有人类低亲和力Fcγ受体均由FCGR2/3基因座（FCGR2/3 locus）编码，该基因座包含功能性单核苷酸多态性（single nucleotide polymorphisms, SNPs）与基因拷贝数变异。该基因座的基因分型向来极具难度，当前常用的高通量检测方法仅能针对少量SNPs开展分析。本研究针对超过4000名受试者的FCGR2/3基因座上所有相关遗传变异实施多重连接依赖性探针扩增（multiplex ligation-dependent probe amplification）检测，以明确不同人群中的连锁不平衡（linkage disequilibrium, LD）模式与等位基因频率。研究团队在该基因座上观察到显著的连锁不平衡现象，且等位基因频率存在广泛的族群差异。其中，FCGR2C-ORF单倍型（rs759550223+rs76277413）的连锁不平衡程度最高，该单倍型可介导FcγRIIc的表达。在欧洲人群中，FCGR2C-ORF单倍型与rs201218628（FCGR2A-Q27W，r²=0.63）等位点存在显著的连锁不平衡；在非洲人群中，这两个变异位点间的连锁不平衡程度较弱（r²=0.17）；而在亚洲人群中，FCGR2C-ORF单倍型几乎不存在（次要等位基因频率（minor allele frequency）<0.005%）。在欧洲人群中，FCGR2C-ORF单倍型与rs1801274（FCGR2A-H131R）仅存在较弱的连锁不平衡（r²=0.08）。本研究针对川崎病（Kawasaki Disease, KD）评估了族群差异与连锁不平衡的影响：川崎病是一种儿童急性血管炎，在亚洲人群中的发病率有所升高。此前已有多族群全基因组关联研究（genome-wide association studies）证实rs1801274与川崎病存在关联。本研究通过对1028名欧洲川崎病患者的分析发现：尽管FCGR2C-ORF单倍型在亚洲人群中几乎不存在，但在欧洲人群中，该单倍型与川崎病易感性的关联强度高于rs1801274。本研究结果表明，在解读针对FCGR2/3基因座的关联研究结果时，结合连锁不平衡与族群差异的相关知识具有重要意义。