Role of activating Fc?R gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response.

ABSTRACT: A functional polymorphism in the inhibitory IgG-Fc receptor gene Fc?RIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki disease (KD), a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (Fc?RIIA, Fc?RIIIA, and Fc?RIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD.We genotyped polymorphisms in the activating Fc?RIIA, Fc?RIIIA, and Fc?RIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The Fc?RIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16-1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the Fc?RIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75-7.66; P=0.0006) and 3.60 (95% CI, 1.34-9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (OR(additive), 2.13; 95% CI, 1.11-4.0; P=0.02).A common variation in Fc?RIIA is associated with increased KD susceptibility. The Fc?RIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating Fc?Rs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.

SUBMITTER: Shrestha S 

PROVIDER: S-EPMC3444514 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature