Transforming growth factor-β signaling pathway in patients with Kawasaki disease

Shimizu, Chisato, Jain, Sonia, Davila, Sonia, Hibberd, Martin L., Lin, Kevin O., Molkara, Delaram, Frazer, Jeffrey R., Sun, Shelly, Baker, Annette L., Newburger, Jane W., Rowley, Anne H., Shulman, Stanford T., Burgner, David, Breunis, Willemijn B. B, Kuijpers, Taco W., Wright, Victoria J., Levin, Michael, Eleftherohorinou, Hariklia, Coin, Lachlan, Popper, Stephen J., Relman, David A., Fury, Wen, Lin, Calvin, Mellis, Scott, Tremoulet, Adriana H. and Burns, Jane C. (2011) Transforming growth factor-β signaling pathway in patients with Kawasaki disease. Circulation: Cardiovascular Genetics, 4 1: 16-25. doi:10.1161/CIRCGENETICS.110.940858

Author Shimizu, Chisato
Jain, Sonia
Davila, Sonia
Hibberd, Martin L.
Lin, Kevin O.
Molkara, Delaram
Frazer, Jeffrey R.
Sun, Shelly
Baker, Annette L.
Newburger, Jane W.
Rowley, Anne H.
Shulman, Stanford T.
Burgner, David
Breunis, Willemijn B. B
Kuijpers, Taco W.
Wright, Victoria J.
Levin, Michael
Eleftherohorinou, Hariklia
Coin, Lachlan
Popper, Stephen J.
Relman, David A.
Fury, Wen
Lin, Calvin
Mellis, Scott
Tremoulet, Adriana H.
Burns, Jane C.
Title Transforming growth factor-β signaling pathway in patients with Kawasaki disease
Journal name Circulation: Cardiovascular Genetics   Check publisher's open access policy
ISSN 1942-325X
Publication date 2011-01-01
Year available 2011
Sub-type Article (original research)
DOI 10.1161/CIRCGENETICS.110.940858
Open Access Status Not yet assessed
Volume 4
Issue 1
Start page 16
End page 25
Total pages 10
Place of publication New York, NY, United States
Publisher Lippincott Williams & Wilkins
Language eng
Abstract Background-Transforming growth factor (TGF)-β 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-β signaling might be important in KD susceptibility and disease outcome. Methods and Results - We investigated genetic variation in 15 genes belonging to the TGF-β 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-β2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptability, 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-β pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-β2 plasma protein levels changed dynamically over the course of the illness. Conclusions-These studies suggest that genetic variation in the TGF-β 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.
Keyword Aortic root dilatation
Coronary artery aneurysm
Kawasaki disease
TGF-β pathway
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID HL074864
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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