title: Role of activating FcγR gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response.
abstract: BACKGROUND
  A 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.
  
  
  RESULTS
  We 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).
  
  
  CONCLUSIONS
  A 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.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, USA.
authors.forename: Sadeep
authors.initials: S
authors.lastname: Shrestha
authors.forename: Howard
authors.initials: H
authors.lastname: Wiener
authors.forename: Aditi
authors.initials: A
authors.lastname: Shendre
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kaslow
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.forename: Aaron
authors.initials: A
authors.lastname: Olson
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Hitendra
authors.initials: H
authors.lastname: Patel
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003324:Coronary Artery Disease / Q000517:prevention & control; D004198:Disease Susceptibility; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009080:Mucocutaneous Lymph Node Syndrome / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D009154:Mutation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; C080568:Fc gamma receptor IIA; D058851:GPI-Linked Proteins; D016756:Immunoglobulins, Intravenous; D017452:Receptors, IgG