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Dysregulation of the Wnt signaling pathway in South African patients with diffuse systemic sclerosis

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Abstract

The objective was to explore changes in gene expression in Wnt pathway genes in skin samples of black South Africans with diffuse cutaneous systemic sclerosis (dcSSc). Affected (forearm) and unaffected (upper back) skin samples of eight Black South Africans with active early dcSSc were compared to skin samples from seven ethnically matched control subjects. The Wnt Pathway Plus RT2 Profiler qPCR Array was used to determine gene expression and analyzed for differential expression between cases and controls. Selective validation was done using single-gene TaqMan assays. Several genes were similarly upregulated in both affected and unaffected skin of the dcSSc patients compared to controls. These included the Wnt ligands WNT7A and WNT10A, the frizzled receptors FZD8 and FZD9, intracellular signaling proteins AXIN1 and AXIN2, and the pathway target genes FGF4 and MMP7. Principal component analysis revealed patients clustering into two groups, which co-segregated with clinical features of interstitial lung disease and/or inflammatory myopathy, or the absence of an inflammation phenotype. These two groups showed paradoxical gene expression of the genes TCF7, SOX17, and FRZB in affected and unaffected skin. This study provides further evidence of dysregulation of gene expression at various levels of the Wnt signaling pathway in dcSSc. Moreover, principal component analysis showed two distinct patient clusters of gene expression, which co-segregated with the presence or absence of clinical inflammatory features, and may reflect different pathological pathways in dcSSc.

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Acknowledgments

We thank Dr. Frank Staedtler (Novartis, Basel) for providing us with the Human Wnt Signaling Pathway RT2 Profiler PCR Array. MT is supported by the Medical Research Council of South Africa. MR is a South African Research Chair in Genomics and Bioinformatics of African populations hosted by the University of the Witwatersrand, funded by the Department of Science and Technology and administered by National Research Foundation of South Africa.

Funding

This work was funded by the Connective Tissue Diseases Grant through the University of the Witwatersrand Faculty of Health Sciences and the National Health Laboratory Service Research Grant. This project was funded by the CRG-Wits-Novartis Visiting Scientist Exchange Program.

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Authors and Affiliations

  1. Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2001, South Africa

    Jacqueline Frost & Michèle Ramsay

  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York City, NY, 10029, USA

    Jacqueline Frost

  3. Genomics and Disease Group, Bioinformatics and Genomics Program, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003, Barcelona, Spain

    Xavier Estivill

  4. Pompeu Fabra University, 08003, Barcelona, Spain

    Xavier Estivill

  5. Experimental Genetics Division, Sidra Medical and Research Center, Doha, 26999, Qatar

    Xavier Estivill

  6. University of the Witwatersrand, Sydney Brenner Institute for Molecular Bioscience, Johannesburg, 2001, South Africa

    Michèle Ramsay

  7. Division of Rheumatology, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, 2001, South Africa

    Mohammed Tikly

Authors
  1. Jacqueline Frost
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  2. Xavier Estivill
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  4. Mohammed Tikly
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Corresponding author

Correspondence to Jacqueline Frost.

Ethics declarations

The study was approved by the Human Research Ethics Committee (Medical), Faculty of Health Sciences, University of the Witwatersrand, and all participants consented in accordance with the Declaration of Helsinki guidelines.

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Frost, J., Estivill, X., Ramsay, M. et al. Dysregulation of the Wnt signaling pathway in South African patients with diffuse systemic sclerosis. Clin Rheumatol 38, 933–938 (2019). https://doi.org/10.1007/s10067-018-4298-5

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  • DOI: https://doi.org/10.1007/s10067-018-4298-5

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