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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

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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.

Conclusion: 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.

What is Known:

• 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.

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Abbreviations

ADAM17:

A disintegrin and metalloprotease 17

BLK:

B lymphoid kinase

CALs:

Coronary artery lesions

FCGR2A:

Fc fragment of IgG, low affinity IIa, receptor

HLA:

Major histocompatibility complex

IVIG:

Intravenous immunoglobulin

KD:

Kawasaki disease

NFAT:

Nuclear factor of activated T cells

SMAD3:

Mothers against decapentaplegic, drosophila, homolog of, 3

SNP:

Single nucleotide polymorphism

TFBS:

Transcription factor binding site

TGFB2:

Transforming growth factor beta-2

TGF-β:

Transforming growth factor-β

TGFBR1:

TGF-beta receptor type-1

TGFBR2:

TGF-beta receptor type-2

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Acknowledgments

We are grateful to all the participants including the children, their parents, and the physicians who provided clinical data for the study. This study was supported by the Science & Technology Department Program of Sichuan Province (No. 2013sz0040) and the Health Department Program of Sichuan Province, China (No. 150197)

Authors’ contribution

QP cared for the patient and was responsible for gathering clinical data. HL, YY, and QP designed the study. YD performed the echocardiography of the patients with KD. QP, XY, and XL were responsible for the genetic experiment. QP performed the statistical analysis and drafted the manuscript. HL and YY made a critical revision. All of the authors discussed the content of the manuscript and approved the final version of the manuscript.

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Authors and Affiliations

  1. 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

    Qian Peng & Hanmin Liu

  2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China

    Qian Peng & Hanmin Liu

  3. Department of Pediatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, 610072, China

    Qian Peng

  4. Department of Cardiovascular Ultrasound and Non-invasive Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, 610072, China

    Yan Deng

  5. Department of Medical Genetics, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China

    Xiling Yang, Xiangyou Leng & Yuan Yang

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  1. Qian Peng
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  2. Yan Deng
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  3. Xiling Yang
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  4. Xiangyou Leng
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  5. Yuan Yang
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  6. Hanmin Liu
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Correspondence to Hanmin Liu.

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The authors declare that they have no competing interests.

Ethical approval

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Clinical Trials and Biomedical Research of Sichuan University and Ethical Review Board of the Sichuan Provincial People’s Hospital, China, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Written informed consent was obtained from the parents of all the subjects who were studied prior to inclusion in the study according to the Declaration of Helsinki.

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Peng, Q., Deng, Y., Yang, X. et al. 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. Eur J Pediatr 175, 705–713 (2016). https://doi.org/10.1007/s00431-016-2696-8

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