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

ABSTRACT: Transforming growth factor (TGF)-? 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-? signaling might be important in KD susceptibility and disease outcome.We investigated genetic variation in 15 genes belonging to the TGF-? 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-?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-? pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-?2 plasma protein levels changed dynamically over the course of the illness.These studies suggest that genetic variation in the TGF-? 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.

SUBMITTER: Shimizu C

PROVIDER: S-EPMC3073847 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Shimizu Chisato C Jain Sonia S Davila Sonia S Hibberd Martin L ML Lin Kevin O KO Molkara Delaram D Frazer Jeffrey R JR Sun Shelly S Baker Annette L AL Newburger Jane W JW Rowley Anne H AH Shulman Stanford T ST Burgner David D Breunis Willemijn B WB Kuijpers Taco W TW Wright Victoria J VJ Levin Michael M Eleftherohorinou Hariklia H Coin Lachlan L Popper Stephen J SJ Relman David A DA Fury Wen W Lin Calvin C Mellis Scott S Tremoulet Adriana H AH Burns Jane C JC

Circulation. Cardiovascular genetics 20101202 1

<h4>Background</h4>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.<h4>Methods and results</h4>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 Unite ...[more]

PMID: 21127203

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Project description:Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling. TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

Dataset Information

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

Publications

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

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