Abstract 1947: Functional Variants in the Inhibitory FcγRIIb Gene Associated With Kawasaki Disease Susceptibility and IVIG Treatment Response
Intravenous immunoglobulin (IVIG) is the main treatment for Kawasaki disease (KD). IVIG interaction with Fcγ receptors on inflammatory cells may play a mechanistic role. About 20% of KD patients in US are refractory to IVIG and display higher coronary artery disease and aneurysm rates than those non-refractory. Host genetic factors play a role in susceptibility to KD. The variable IVIG effect further supports our hypothesis that altered FCγR function caused by genetic variation affects susceptibility and treatment response. We enrolled 97 case-parent trios and 73 case-single parent pair KD patients and treatment responses were defined according to AHA guidelines. DNA was extracted from participant whole blood or saliva. Relevant SNPs in the 6 FCγR genes were genotyped using pyrosequencing method. Preliminary analyses showed the greatest signal from the FcγRIIb gene with three functionally relevant SNPs (−386G >C, −120T >A in the promoter and 775T >C in the transmembrane domain). We used the FBAT program to perform a transmission disequilibrium test (TDT) on individual SNPs and to estimate haplotype frequencies and search for excess transmission of multi-SNP haplotypes. In univariate analysis, the C allele (frequency =15%) of SNP 775T >C (rs1050501) was marginally less transmitted from heterozygous parents to KD patients (z = 1.757, p = 0.07) and one haplotype containing the SNP775C allele (frequency = 13%) was significantly transmitted less frequently (z = 2.408, p = 0.02), suggesting that this haplotype may be protective against development of KD. The same haplotype was associated with the differential IVIG treatment response (z = 1.92, p = 0.05) also suggesting that KD patients with this haplotype may respond more effectively to IVIG treatment. The FcγRIIb gene encodes an inhibitory immunoglobulin receptor with low IgG affinity, and previously thought to interact minimally with IVIG. Our results show that variants in FcγRIIb influence both KD susceptibility and IVIG treatment response. These data suggest a new paradigm for our understanding of KD and further research is warranted with focus on this single inhibitory IgG receptor operating at the interface of innate and adaptive immunity along with interactions with other Fcγ receptors.