Session Information
Session Type: Abstract Submissions (ACR)
Abstract on behalf of the International Kawasaki Disease Genetics Consortium.
Background/Purpose: Kawasaki disease (KD) is a pediatric vasculitis of unknown etiology with a substantial genetic contribution to susceptibility. KD is complicated by coronary artery aneurysms in 25% of untreated patients. Intravenous immunoglobulin (IVIG), a polyclonal IgG preparation, decreases the aneurysm rate to <10%. In our recent GWAS, a functional variant in FCGR2A (131H>R; rs1801274) was associated with KD at genome-wide significance. FCGR2A encodes the Fc-gamma receptor (FcγR) IIa, one member of a family of glycoproteins on leukocytes that bind the Fc-domain of IgG. The balance between the various activating and a single inhibiting FcγR (FcγRIIb) determines the level of cell activation. Hence, altered FcγR expression may result in unbalanced immunity or auto-inflammation. FCGR2A is located within the FCGR2/3 gene cluster. This cluster contains extensive gene copy number variations (CNVs) and several important single nucleotide polymorphisms (SNPs). We hypothesized that CNV and additional SNPs within the FCGR locus, regulating gene transcription and expression of the FcγRs, may be important in KD susceptibility.
Methods: The FCGR-specific Multiplex-Ligation Probe-dependent Amplification (MLPA) assay was performed in 426 patients and 710 controls of Caucasian origin, and in 510 patient-parent trios of mixed ethnic origin. First, the association between FCGR genotype status (including CNV, FCGR2A-131H>R, FCGR2A-27Q>W, FCGR2C-ORF and FCGR2B -386G>C) and KD susceptibility was analyzed. Second, the genetic variation at the FCGR2/3 locus was correlated to the expression of these genes. Transcriptional expression data (pre-IVIG acute and post-IVIG convalescent samples) were available in a subset of 169 patients.
Results: An increased allele frequency of the open-reading frame (ORF) of FCGR2C encoding an additional activating FcγRIIc was found in patients as compared to controls (OR 1.4 [95%CI 1.1-1.7], p=0.016). We also observed a significant overrepresentation of FCGR2A-27Q>W (OR 1.5 [95%CI 1.1-1.9, p=0.006) and the -386G>C promoter polymorphism of FCGR2B and FCGR2C (OR 1.5 [95%CI 1.1-1.9], p=0.004) in KD. No significant difference was found in the allele frequency of FCGR2A-131H>R in KD patients and controls (43.8% versus 45.4%, p=0.467). The frequency of CNV in the FCGR2C, FCGR3A and FCGR3B genes was not significantly different between the groups. A positive correlation was observed between gene expression and dosage of FCGR2C, FCGR3A and FCGR3B, which may affect the activating FcγRs expression level on leucocytes. Results of the patient-parent trios data using transmission disequilibrium tests (TDT) will be used for further validation of our fine-mapping studies on the FCGR2/3genes in KD.
Conclusion: A significant overrepresentation of FCGR2C-ORF, as well as FCGR2A-27Q>W and the FCGR2B/C-386G>C promoter polymorphisms, was observed in Caucasian KD patients compared to the controls. Genetic variation at the FCGR2/3 gene cluster may lead to a shift in the balance towards the activating FcγRs and may therefore contribute to the development of the inflammatory response in KD.
Disclosure:
C. E. Tacke,
None;
W. B. Breunis,
None;
L. T. Hoang,
None;
E. Png,
None;
J. Geissler,
None;
S. Nagelkerke,
None;
J. Ellis,
None;
S. Davila,
None;
C. C. Khor,
None;
M. Levin,
None;
D. Burgner,
None;
C. Shimizu,
None;
J. C. Burns,
None;
M. L. Hibberd,
None;
T. W. Kuijpers,
None.
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