Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.

Yue Wang,Karl G Sylvester,John T Kanegaye,Shiying Hao,Xiyuan Jiang,Jane C Burns,Adriana H Tremoulet,John C Whitin,Harvey J Cohen,Xiaofeng Li,Min Huang,Guang Hu,Zhen Li,Yunxian Yu,Xuejun Jiang,Doff B Mcelhinney,Xuefeng B Ling,Junghwa Lee,Xin Deng ,Ran Miao ,Andrew Shin ,Kee Soo Ha

doi:10.1371/journal.pone.0167434

Abstract

BackgroundResistance to intravenous immunoglobulin (IVIG) occurs in 10–20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.MethodWe explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.ResultsThirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.ConclusionsGene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics.

Highlights

Kawasaki disease (KD) is an acute systemic vasculitis of infants and children, that occurs world-wide [1], but the biology of this condition is not well understood
Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by intravenous immunoglobulin (IVIG) may be a mechanism of action of IVIG in KD; (2) changes in sialylation and gamma glutamyl transferase (GGT) level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis
We [10,11,12] and others [13,14,15] have found that serum gamma-glutamyl transferase (GGT) levels are elevated in the acute phase of KD patients and that higher GGT levels are associated with IVIG resistance

Summary

Introduction

Kawasaki disease (KD) is an acute systemic vasculitis of infants and children, that occurs world-wide [1], but the biology of this condition is not well understood. We [10,11,12] and others [13,14,15] have found that serum gamma-glutamyl transferase (GGT) levels are elevated in the acute phase of KD patients and that higher GGT levels are associated with IVIG resistance. We explored the association of GGT level and IVIG resistance in KD patients to try to understand the biological mechanism of action underlying these two clinical findings. Resistance to intravenous immunoglobulin (IVIG) occurs in 10–20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels

Methods

Results

Conclusion