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Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease. Inflamm Bowel Dis 2019 02 21;25(3):547-560

Date

08/21/2018

Pubmed ID

30124884

Pubmed Central ID

PMC6391846

DOI

10.1093/ibd/izy265

Scopus ID

2-s2.0-85061961459   5 Citations

Abstract

BACKGROUND: Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling.

METHODS: Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined.

RESULTS: We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001).

CONCLUSIONS: Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

Author List

Denson LA, Jurickova I, Karns R, Shaw KA, Cutler DJ, Okou D, Valencia CA, Dodd A, Mondal K, Aronow BJ, Haberman Y, Linn A, Price A, Bezold R, Lake K, Jackson K, Walters TD, Griffiths A, Baldassano RN, Noe JD, Hyams JS, Crandall WV, Kirschner BS, Heyman MB, Snapper S, Guthery SL, Dubinsky MC, Leleiko NS, Otley AR, Xavier RJ, Stevens C, Daly MJ, Zwick ME, Kugathasan S

Author

Joshua D. Noe MD Associate Dean, Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Case-Control Studies
Child
Child, Preschool
Crohn Disease
Cytokine Receptor Common beta Subunit
Female
Follow-Up Studies
Granulocyte-Macrophage Colony-Stimulating Factor
Humans
Infant
Male
Mutation, Missense
Neutrophils
Prognosis
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Transcriptome
Young Adult