Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 4, Issue 1, Pages 16-U99Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.110.940858
Keywords
Kawasaki disease; TGF-beta pathway; aortic root dilatation; coronary artery aneurysm; genetics
Funding
- National Institutes of Health National Heart, Lung, Blood Institute [HL074864, HL091494, HL69413]
- Singapore Agency for Science Technology and Research (A*STAR)
- London Law Trust
- Sir Samuel Scott of Yews Trust
- University of Western Australia
- National Heart Foundation Australia
- Princess Margaret Hospital Perth
- Raine Medical Research Foundation
- Ada Bartholomew Medical Research Trust
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Background-Transforming growth factor (TGF)-beta is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-beta signaling might be important in KD susceptibility and disease outcome. Methods and Results-We investigated genetic variation in 15 genes belonging to the TGF-beta pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase-polymerase chain reaction for these same genes, and measured TGF-beta 2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (P=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-beta pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-beta 2 plasma protein levels changed dynamically over the course of the illness. Conclusions-These studies suggest that genetic variation in the TGF-beta pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery Z scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis. (Circ Cardiovasc Genet. 2011; 4: 16-25.)
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