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. Kendrick; James Tonascia; Frank A. Hamilton; Gianrico Farrugia

doi:10.1186/s12920-018-0379-1

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 journal › Article › peer-review

14 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 language	English (US)
Article number	62
Journal	BMC medical genomics
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s12920-018-0379-1
State	Published - Aug 7 2018

Keywords

Diabetes mellitus
Macrophages
Next generation sequencing
RNA
Signaling

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1186/s12920-018-0379-1

Cite this

Grover, M., Gibbons, S. J., Nair, A. A., Bernard, C. E., Zubair, A. S., Eisenman, S. T., Wilson, L. A., Miriel, L., Pasricha, P. J., Parkman, H. P., Sarosiek, I., McCallum, R. W., Koch, K. L., Abell, T. L., Snape, W. J., Kuo, B., Shulman, R. J., McKenzie, T. J., Kellogg, T. A., ... Farrugia, G. (2018). Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis. BMC medical genomics, 11(1), Article 62. https://doi.org/10.1186/s12920-018-0379-1

Grover, M, Gibbons, SJ, Nair, AA, Bernard, CE, Zubair, AS, Eisenman, ST, Wilson, LA, Miriel, L, Pasricha, PJ, Parkman, HP, Sarosiek, I, McCallum, RW, Koch, KL, Abell, TL, Snape, WJ, Kuo, B, Shulman, RJ, McKenzie, TJ, Kellogg, TA, Kendrick, ML, Tonascia, J, Hamilton, FA & Farrugia, G 2018, 'Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis', BMC medical genomics, vol. 11, no. 1, 62. https://doi.org/10.1186/s12920-018-0379-1

@article{fac1888bf8c74034aeda13f49a7b7c5e,

title = "Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis",

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{\textregistered}. 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.",

keywords = "Diabetes mellitus, Macrophages, Next generation sequencing, RNA, Signaling",

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

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = aug,

day = "7",

doi = "10.1186/s12920-018-0379-1",

language = "English (US)",

volume = "11",

journal = "BMC medical genomics",

issn = "1755-8794",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis

AU - Grover, Madhusudan

AU - Gibbons, Simon J.

AU - Nair, Asha A.

AU - Bernard, Cheryl E.

AU - Zubair, Adeel S.

AU - Eisenman, Seth T.

AU - Wilson, Laura A.

AU - Miriel, Laura

AU - Pasricha, Pankaj J.

AU - Parkman, Henry P.

AU - Sarosiek, Irene

AU - McCallum, Richard W.

AU - Koch, Kenneth L.

AU - Abell, Thomas L.

AU - Snape, William J.

AU - Kuo, Braden

AU - Shulman, Robert J.

AU - McKenzie, Travis J.

AU - Kellogg, Todd A.

AU - Kendrick, Michael L.

AU - Tonascia, James

AU - Hamilton, Frank A.

AU - Farrugia, Gianrico

PY - 2018/8/7

Y1 - 2018/8/7

N2 - 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.

AB - 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.

KW - Diabetes mellitus

KW - Macrophages

KW - Next generation sequencing

KW - RNA

KW - Signaling

UR - http://www.scopus.com/inward/record.url?scp=85051223026&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051223026&partnerID=8YFLogxK

U2 - 10.1186/s12920-018-0379-1

DO - 10.1186/s12920-018-0379-1

M3 - Article

C2 - 30086735

AN - SCOPUS:85051223026

SN - 1755-8794

VL - 11

JO - BMC medical genomics

JF - BMC medical genomics

IS - 1

M1 - 62

ER -

Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this