Abstract 15915: A Polymorphism in Activating Fcgr2a Associates With Kawasaki Disease (KD) Susceptibility, IVIG Response, and Coronary Artery Inflammation
Host genetic factors play a role in KD susceptibility and treatment response. Our prior studies showed that a polymorphism in the promoter of the inhibitory FcγRIIB influenced IVIG treatment response selectively in Caucasians. FcγRIIB co-ligates with activating FCγRs to modify immunes response. We hypothesized that polymorphisms in the activating receptors could alter susceptibility, IVIG treatment response, or coronary artery disease in KD patients. We examined 11 functional polymorphisms in FCgRIIA, FCgRIIIA and FCgRIIIB, all located at chromosome position 1q23 within a span of about 200kb, in 371 KD patients (279 trios, 92 case-single parent pairs). Genetic variants were genotyped by pyrosequencing using a nested polymerase chain reaction (PCR) approach to ensure gene-specific amplification. We used the FBAT program to perform a transmission disequilibrium test (TDT), which tests for disequilibrium of allele transmission from heterozygous parents to affected child. In the additive TDT model, the FcγRIIA+559 variant showed excess A allele (Histidine) transmission from parents (z = 3.12, p = 0.001) to KD patients in informative (n = 182) trios. This effect was consistent separately in Asian (n = 26; z = 2.34, p=0.02) and Caucasian families (n = 105; z = 2.04, p = 0.04). Likewise, excess transmission of the same A allele in FcγRIIA+559 occurred among IVIG non-responders (n = 156; z = 2.78, p=0.005), defined by AHA guidelines, and patients with CAD (n = 43, z = 2.45, p = 0.01), defined by persistence of coronary artery Z-score > 2.5 or aneurysm > 6 weeks after IVIG. Other variants examined did not indicate any significant associations. FcγRIIA contains an ITAM motif characteristic of an activation receptor, and the polymorphism FcγRIIA+559(A/g) variant alters recognition of ligand where, FcγRIIA+559A variant binds human IgG2, but less with FcγRIIA+559G variant. FcγRIIA+559G variant, which has a less effective phagocytosis IgG2 opsonized particles, has been associated with immunological disease like SLE and lupus nephritis in several ethnic groups. In contrary, excess transmission of the more effective FcγRIIA+559A variant was related to increased KD susceptibility, IVIG refractoriness, and CAD persistence in our study.
- © 2011 by American Heart Association, Inc.