Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Functional Polymorphisms in the Inhibitory FCGR2B Associate with Efficacy of IVIG Treatment Response among Patients with Kawasaki Disease.

Shrestha2,  Sadeep, Wiener1,  Howard W., Shendre1,  Aditi, Kaslow1,  Richard A., Olson3,  Aaron K., Lee3,  Mary Beth, Edberg4,  Jeffrey C.

Department of Epidemiology, University of Alabama at Birmingham
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
Department of Pediatrics, University of Washington, Seattle Children's Hospital
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham

Background:

Intravenous immunoglobulin (IVIG) is the principal treatment for Kawasaki disease (KD). Approximately 20% of KD patients in US are refractory to IVIG, and display higher coronary artery disease and aneurysm rates than those non-refractory. Studies in animal model systems have demonstrated a requirement for expression of the inhibitory Fcg receptor FCGR2B in IVIG therapeutic responses. We hypothesized that naturally occurring functional SNP variants in the human FCGR2B gene would influence efficacy of IVIG treatment in patients with KD.

Methods:

We examined three well-characterized and functionally relevant SNPs in the inhibitory FCGR2B gene among 197 patients (104 European-American (EA), 47 Asians, 46 Other) with KD (based on criteria recommended by the American Heart Association) that had been treated with IVIG as standard of care. Among these patients, 56 were defined as non-responders (persistent fever (temperature >38°C) at >36 hours from the initiation of IVIG infusion or recurrent fever at >36 hours after completion of the initial IVIG infusion) and 141 as responders. SNPs chosen for study are 2 promoter variants at -120 and -386 that alter transcription factor binding and quantitative gene expression and a non-synonymous SNP in the transmembrane region of the protein that alters lipid domain association and quantitative inhibitory potential. Genotyping was performed by Pyrosequencing. Race and ethnicity were genetically determined using Principle component analysis with 162 ancestry informative markers.

Results:

Significant association between all of the functional FCGR2B variants and IVIG response were observed in EA patients. Both the more active promoter variants (-120A/-386C, OR = 4.46 [1.30–15.3], p=0.01/OR=4.38 [1.28–15.1], p=0.01 respectively) and the more functionally active non-synonymous variant in the transmembrane domain (+775T, OR = 2.38 [1.00–5.88], p=0.05) were positively associated with IVIG response. The 2 promoter variants are in complete linkage disequilibrium and are not independent effects. Because of lower allele frequency and smaller sample size in the other populations, we did not have sufficient power to demonstrate associations between FCGR2B variants and IVIG responses.

Conclusions:

Our data are the first to demonstrate a genetic basis in humans for IVIG responses in KD. The known functional consequences of the variants in FCGR2B that associate with IVIG response result in high receptor expression and function and thus are biological plausible and consistent with murine model studies demonstrating a requirement for FCGR2B in IVIG efficacy. Replication of these findings could suggest a role for screening of patients for FCGR2B genotypes prior to treatment.

To cite this abstract, please use the following information:
Shrestha, Sadeep, Wiener, Howard W., Shendre, Aditi, Kaslow, Richard A., Olson, Aaron K., Lee, Mary Beth, et al; Functional Polymorphisms in the Inhibitory FCGR2B Associate with Efficacy of IVIG Treatment Response among Patients with Kawasaki Disease. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :828
DOI: 10.1002/art.28596

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