Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis

Madhusudan Grover, Simon J. Gibbons, Asha A. Nair, Cheryl E. Bernard, Adeel S. Zubair, Seth T. Eisenman, Laura A. Wilson, Laura Miriel, Pankaj J. Pasricha, Henry P. Parkman, Irene Sarosiek, Richard W. McCallum, Kenneth L. Koch, Thomas L. Abell, William J. Snape, Braden Kuo, Robert J. Shulman, Travis J. McKenzie, Todd A. Kellogg, Michael L. KendrickJames Tonascia, Frank A. Hamilton, Gianrico Farrugia

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background: Cellular changes described in human gastroparesis have revealed a role for immune dysregulation, however, a mechanistic understanding of human gastroparesis and the signaling pathways involved are still unclear. Methods: Diabetic gastroparetics, diabetic non-gastroparetic controls, idiopathic gastroparetics and non-diabetic non-gastroparetic controls underwent full-thickness gastric body biopsies. Deep RNA sequencing was performed and pathway analysis of differentially expressed transcripts was done using Ingenuity®. A subset of differentially expressed genes in diabetic gastroparesis was validated in a separate cohort using QT-PCR. Results: 111 genes were differentially expressed in diabetic gastroparesis and 181 in idiopathic gastroparesis with a log2fold difference of | ≥ 2| and false detection rate (FDR) < 5%. Top canonical pathways in diabetic gastroparesis included genes involved with macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, osteoarthritis pathway and differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F. Top canonical pathways in idiopathic gastroparesis included genes involved in granulocyte adhesion and diapedesis, agranulocyte adhesion and diapedesis, and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Sixty-five differentially expressed genes (log2fold difference | ≥ 2|, FDR < 5%) were common in both diabetic and idiopathic gastroparesis with genes in the top 5 canonical pathways associated with immune signaling. 4/5 highly differentially expressed genes (SGK1, APOLD1, CXCR4, CXCL2, and FOS) in diabetic gastroparesis were validated in a separate cohort of patients using RT-PCR. Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p < 0.05). Conclusions: Diabetic and idiopathic gastroparesis have both unique and overlapping transcriptomic signatures. Innate immune signaling likely plays a central role in pathogenesis of human gastroparesis.

Original languageEnglish (US)
Article number62
JournalBMC medical genomics
Volume11
Issue number1
DOIs
StatePublished - Aug 7 2018

Keywords

  • Diabetes mellitus
  • Macrophages
  • Next generation sequencing
  • RNA
  • Signaling

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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