title: Genetic variants of ADAM17 are implicated in the pathological process of Kawasaki disease and secondary coronary artery lesions via the TGF-β/SMAD3 signaling pathway.
abstract: Kawasaki disease (KD) is a systemic vasculitis childhood disease frequently complicating coronary artery lesions (CALs). Recently, the gene encoding a disintegrin and metalloprotease 17 (ADAM17) was found to modify vascular pathology in humans by differentially regulating the transforming growth factor-β (TGF-β) signaling pathway, which affects KD/CAL susceptibility. To explore the potential role of ADAM17 in KD occurrence and outcomes, we investigated the association of 28 single nucleotide polymorphisms (SNPs) in ADAM17 and three pathway genes of TGF-β signaling with KD phenotypes in a Han Chinese population, including 392 KD patients and 421 non-KD controls. Three ADAM17 SNPs showed an association with KD risk, which was further confirmed by haplotype analysis. The effect of ADAM17 on KD was also shown by multi-variable logistic regression analysis. In two-locus model analyses with SNPs in ADAM17 and TGF-β signaling pathway genes, stronger compound effects on the risk of KD and secondary CAL formation were observed relative to comparable single SNPs.
  
  
  CONCLUSIONS
  Our results suggest that ADAM17 contributes to the KD risk and is involved in secondary CAL formation via the TGF-β/SMAD3 signaling pathway. This further enriches our understanding of the importance of the signaling pathway in KD occurrence and outcomes.
  
  
  BACKGROUND
  • The transforming growth factor (TGF)-β/SMAD3 signaling pathway greatly influences susceptibility to Kawasaki disease (KD) and secondary coronary artery lesions (CALs) and/or the treatment response of intravenous immunoglobulin. • A disintegrin and metalloprotease 17 (ADAM17) effectively reduces TGF-β signaling by cleaving TGF-β receptor type-1, while ADAM17 genetic variants modify human vascular pathology by differentially regulating this signaling although it is unknown whether ADAM17 contributes to KD phenotypes. What is New: • ADAM17 genetic variants were shown to be associated with KD risk, even when excluding the influence of TGF-β signaling pathway genes, suggesting that ADAM17 is an important KD susceptibility-related genetic locus. • The more significant compound effects of two-locus models, combining single nucleotide polymorphisms (SNPs) in ADAM17 and other TGF-β signaling pathway genes including TGFB2 and SMAD3, on KD phenotypes relative to single SNPs suggest that ADAM17 is also involved in secondary CAL formation and confers the risk of KD/CALs via the TGF-β/SMAD3 signaling pathway.
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital/West China Women's and Children's Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China.|Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.|Department of Pediatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Cardiovascular Ultrasound and Non-invasive Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Medical Genetics, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China.
authors.forename: Xiling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medical Genetics, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China.
authors.forename: Xiangyou
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Medical Genetics, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital/West China Women's and Children's Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China. liuhscu@163.com.|Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China. liuhscu@163.com.
authors.forename: Hanmin
authors.initials: H
authors.lastname: Liu
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D003331:Coronary Vessels / Q000000981:diagnostic imaging*; D004247:DNA / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D004247:DNA; D000072198:ADAM17 Protein
keywords: ADAM17; Coronary artery lesions; Kawasaki disease; SMAD3; TGF-β signaling pathway
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