title: Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.
abstract: BACKGROUND
  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
  We 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.
  
  
  RESULTS
  Thirty-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.
  
  
  CONCLUSIONS
  Gene 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.
authors.affiliation: School of public health, school of medicine, Zhejiang University, Hangzhou, China.|Stanford University, Stanford, CA, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Stanford University, Stanford, CA, United States of America.|School of Electrical Engineering, Southeast University, Nanjing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Shiying
authors.initials: S
authors.lastname: Hao
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Deng
authors.affiliation: Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Miao
authors.initials: M
authors.lastname: Ren
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: University of California San Diego, La Jolla, CA, United States of America.|Rady Children's Hospital San Diego, San Diego, CA, United States of America.
authors.forename: John T
authors.initials: JT
authors.lastname: Kanegaye
authors.affiliation: Department of Pediatrics, Korea University Medical Center, Guro Hospital, Seoul, Korea.
authors.forename: Kee-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Pediatrics, Korea University Medical Center, Guro Hospital, Seoul, Korea.
authors.forename: JungHwa
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Heart Center, Beijing Children's Hospital, Beijing, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: School of public health, school of medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yunxian
authors.initials: Y
authors.lastname: Yu
authors.affiliation: University of California San Diego, La Jolla, CA, United States of America.|Rady Children's Hospital San Diego, San Diego, CA, United States of America.
authors.forename: Adriana H
authors.initials: AH
authors.lastname: Tremoulet
authors.affiliation: University of California San Diego, La Jolla, CA, United States of America.|Rady Children's Hospital San Diego, San Diego, CA, United States of America.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Whitin
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Shin
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Sylvester
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Doff B
authors.initials: DB
authors.lastname: McElhinney
authors.affiliation: Stanford University, Stanford, CA, United States of America.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Cohen
authors.affiliation: School of public health, school of medicine, Zhejiang University, Hangzhou, China.|Stanford University, Stanford, CA, United States of America.
authors.forename: Xuefeng B
authors.initials: XB
authors.lastname: Ling
mesh_terms: D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D017209:Apoptosis; D002097:C-Reactive Protein / Q000032:analysis; D002675:Child, Preschool; D015331:Cohort Studies; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D009504:Neutrophils / Q000166:cytology; D016017:Odds Ratio; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000097:blood*
chemical_list: D016756:Immunoglobulins, Intravenous; D017382:Reactive Oxygen Species; D002097:C-Reactive Protein; D005723:gamma-Glutamyltransferase; C098871:Neu5Ac N-acetylgalactosamine 2,6-sialyltransferase; D012799:Sialyltransferases; D000410:Alanine Transaminase