Transforming growth factor-beta signaling pathway in patients with Kawasaki disease.
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.


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 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-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.
University of California and Rady Children's Hospital San Diego, San Diego, CA, USA.
Chisato
C
Shimizu
Sonia
S
Jain
Sonia
S
Davila
Martin L
ML
Hibberd
Kevin O
KO
Lin
Delaram
D
Molkara
Jeffrey R
JR
Frazer
Shelly
S
Sun
Annette L
AL
Baker
Jane W
JW
Newburger
Anne H
AH
Rowley
Stanford T
ST
Shulman
Sonia
S
Davila
David
D
Burgner
Willemijn B
WB
Breunis
Taco W
TW
Kuijpers
Victoria J
VJ
Wright
Michael
M
Levin
Hariklia
H
Eleftherohorinou
Lachlan
L
Coin
Stephen J
SJ
Popper
David A
DA
Relman
Wen
W
Fury
Calvin
C
Lin
Scott
S
Mellis
Adriana H
AH
Tremoulet
Jane C
JC
Burns
D001011:Aorta / Q000473:pathology; D001315:Australia; D015331:Cohort Studies; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D015810:Linkage Disequilibrium / Q000235:genetics; D009080:Mucocutaneous Lymph Node Syndrome / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051900:Smad3 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000235:genetics; D006113:United Kingdom; D014481:United States
D016756:Immunoglobulins, Intravenous; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II