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

Abstract

Objective 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. Methods The copy number of individuals with KD (n = 510) and their family members (n = 808) for three variable FcγRs was assessed using pyrosequencing. We performed the transmission disequilibrium test to examine the association of GCN for FcγRs (FcγR2C, FcγR3A, and FcγR3B) with susceptibility and used logistic regression models to determine its association with IVIG treatment outcomes. Results FcγR2C and FcγR3B GCN were significantly associated with KD susceptibility. IVIG response was associated with GCN variations of FcγR3B in Whites and FcγR2C in Hispanics, and gene risk score based on single nucleotide polymorphism and GCN in FcγRs were significantly different between IVIG responders and nonresponders among Whites. We found no significant associations between coronary artery disease and any of the FcγR copy numbers. Conclusion GCN of FcγR2C and FcγR3B influences IVIG treatment response and predisposes individuals to KD, providing potential insights into understanding the mechanism of the FcγR gene family in the IVIG pathway.

Imputation of class I and II HLA loci using high‐density SNPs from ImmunoChip and their associations with Kawasaki disease in family‐based study

“…Parents of KD patients in Japan have two-fold higher prevalence than general populations (Uehara et al , 2003). Additionally, multiple genome-wide association (GWA) and candidate gene studies, including our own, have consistently identified the Fc gamma receptors (FcGRs) as major players in the pathogenesis and treatment response for KD (Khor et al , 2011; Makowsky et al , 2013; Onouchi et al , 2012; Shendre et al , 2014; Shrestha et al , 2012; Shrestha et al , 2011). However, there are reports of other genes that have not been adequately studied, including the human leukocyte antigen (HLA) genes in the major histocompatibility complex (MHC) region.…”

European consensus proposal for immunoglobulin therapies

“…Similarly, in acute myasthenia gravis, 2 g/kg IVIg did not show a better efficacy than 1 g/kg , underlining the urgent need of more studies addressing the dosing issue. In the future, better target values supported by biomarkers of IVIg resistance could also contribute to significant savings. The WG agreed that there is little point in prescribing Ig if the amount given is not sufficient to produce a sustained clinical benefit.…”

“…Understanding the underlying mechanisms for these differences may change this view, particularly in replacement therapy for PID, and should be subject to more research. Issues such as difference in specific antibody titers, IgG glycosylation, the patient's Fc‐γ‐receptor polymorphisms, and copy number variation may be involved . In terms of product choice, so far no benefit can be drawn from the very few, usually small scale, head‐to‐head studies comparing products.…”

One Size Does Not Fit All

“…Genetic risk score analysis using multiple functional and copy number variants (CNV) of FcγR gene families showed that the prediction models were statistically significant for both KD susceptibility and IVIG response among non-Hispanic Caucasians but not in others. 19 The differences depend largely on deviations in SNP frequency and CNV among racial and ethnic groups. For example, FcγR2B -120T/a allele is not polymorphic in EAS and occurs rarely in Hispanics, therefore contributing minimally to a predictive model in those populations.…”

“…The results reveal genetic heterogeneity as many of these SNPs do not occur in genes indicated in other IVIG resistance studies. 13, 19 This discrepancy could be due to limitations in the GWA platform. In particular, given the complexity of genomic sequences with copy numbers and near 100% sequence homology across FcGR gene families, some of these variants are not well-captured in genotyping arrays and require complex methodologies.…”