Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Abstract

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Precision Medicine for Kawasaki Disease

“…This is an exciting time in KD research because a practicable biomarker (eg., IP-10) with extremely high sensitivity and specificity has been identified (26), and the genetic contributions to KD are becoming clearer than ever (23, 39,52,53). Follow-up research based on these achievements could clarify the pathogenic mechanisms that lead to KD.…”

“…To identify novel genetic factors that predispose an individual to KD, GWASs for KD in a Han Chinese (51,52) and Japanese population (53) were recently conducted, and novel critical susceptibility loci located in the CD40, B-lymphocyte kinase (BLK), FCGR2A, as well as ITPKC gene regions were identified. These findings highlighted the importance of B-cell or T-cell activation by candidate genes to the pathogenesis of this inflammatory disease (Figure 1).…”

Association between the FCGR2A gene H131R polymorphism and risk of Kawasaki disease: a meta-analysis

“…As shown in Figure 1, a final total of 2122 patients with KD and 1565 controls were included in the metaanalysis (Taniuchi et al, 2005;Biezeveld et al, 2007;Khor et al, 2011;Ji et al, 2013;Yan et al, 2013;Chatzikyriakidou et al, 2014). The characteristics of these eight case-control studies from six articles are presented in Table 1; these contain studies of two Caucasian (Biezeveld et al, 2007;Chatzikyriakidou et al, 2014) and six Asian (Taniuchi et al, 2005;Khor et al, 2011;Ji et al, 2013;Yan et al, 2013) populations. The distribution of genotypes in the controls was consistent with HWE in all studies except for Taniuchi et al (2005).…”

“…Until now, genome-wide association studies and linkage analyses have reported a few genetic loci that have shown association with KD in subjects of Japanese, European, Korean, and Taiwanese descent (Burgner et al, 2009), including the IgG receptor gene FCGR2A. A point mutation (A→G) in FCGR2A (reference/alternative) resulting in an amino acid change at position 131, histidine (His131) to arginine (Arg131), is located in the second extracellular immunoglobulin-like domain of the FCGR2A protein (H131R); it has been suggested that this variation this variation might be related to the development of KD (Khor et al, 2011).…”

Cardiovascular Lesions of Kawasaki Disease: From Genetic Study to Clinical Management

“…IVIG appears to have a generalized anti-inflammatory effect. Possible mechanisms of action include modulation of cytokine production, neutralization of bacterial super-antigens or other etiologic agents, augmentation of regulatory T cell activity (TGF-), (23,26) suppression of antibody synthesis and inflammatory markers (CD40-CD40L, nitric oxide, and iNOS expression),(60-62) provision of anti-idiotypic antibodies, Fc-gamma receptor, (63) and balancing Th1/Th2 responses. (28)(29)(30) KD patients should be treated with a single 12-hour infusion of 2 g/kg IVIG together with aspirin in the acute phase with fever or inflammation progression without fever.…”