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Fc?R gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response.

ABSTRACT: Kawasaki disease (KD), response to intravenous immunoglobulin (IVIG) therapy, and associated coronary artery disease progression have been associated with genetic polymorphisms in Fc gamma receptor (Fc?R) genes. However, it is not known whether the existing gene copy number (GCN) variability relates to KD treatment response, susceptibility, or associated sequelae.The copy number of individuals with KD (n=510) and their family members (n=808) for three variable Fc?Rs was assessed using pyrosequencing. We performed the transmission disequilibrium test to examine the association of GCN for Fc?Rs (Fc?R2C, Fc?R3A, and Fc?R3B) with susceptibility and used logistic regression models to determine its association with IVIG treatment outcomes.Fc?R2C and Fc?R3B GCN were significantly associated with KD susceptibility. IVIG response was associated with GCN variations of Fc?R3B in Whites and Fc?R2C in Hispanics, and gene risk score based on single nucleotide polymorphism and GCN in Fc?Rs were significantly different between IVIG responders and nonresponders among Whites. We found no significant associations between coronary artery disease and any of the Fc?R copy numbers.GCN of Fc?R2C and Fc?R3B influences IVIG treatment response and predisposes individuals to KD, providing potential insights into understanding the mechanism of the Fc?R gene family in the IVIG pathway.

SUBMITTER: Makowsky R

PROVIDER: S-EPMC4400828 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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FcγR gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response.

Makowsky Robert R Wiener Howard W HW Ptacek Travis S TS Silva Miriam M Shendre Aditi A Edberg Jeffrey C JC Portman Michael A MA Shrestha Sadeep S

Pharmacogenetics and genomics 20130901 9

<h4>Objective</h4>Kawasaki disease (KD), response to intravenous immunoglobulin (IVIG) therapy, and associated coronary artery disease progression have been associated with genetic polymorphisms in Fc gamma receptor (FcγR) genes. However, it is not known whether the existing gene copy number (GCN) variability relates to KD treatment response, susceptibility, or associated sequelae.<h4>Methods</h4>The copy number of individuals with KD (n=510) and their family members (n=808) for three variable F ...[more]

PMID: 23778324

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Project description:BackgroundA functional polymorphism in the inhibitory IgG-Fc receptor gene FcγRIIB 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 (FcγRIIA, FcγRIIIA, and FcγRIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD.Methods and resultsWe genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA, and FcγRIIIB 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 FcγRIIA-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 FcγRIIIB 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).ConclusionsA common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.

Dataset Information

Fc?R gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response.

Publications

FcγR gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response.

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