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Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease.

  • Author(s): Denson, Lee A
  • Jurickova, Ingrid
  • Karns, Rebekah
  • Shaw, Kelly A
  • Cutler, David J
  • Okou, David
  • Valencia, C Alexander
  • Dodd, Anne
  • Mondal, Kajari
  • Aronow, Bruce J
  • Haberman, Yael
  • Linn, Aaron
  • Price, Adam
  • Bezold, Ramona
  • Lake, Kathleen
  • Jackson, Kimberly
  • Walters, Thomas D
  • Griffiths, Anne
  • Baldassano, Robert N
  • Noe, Joshua D
  • Hyams, Jeffrey S
  • Crandall, Wallace V
  • Kirschner, Barbara S
  • Heyman, Melvin B
  • Snapper, Scott
  • Guthery, Stephen L
  • Dubinsky, Marla C
  • Leleiko, Neal S
  • Otley, Anthony R
  • Xavier, Ramnik J
  • Stevens, Christine
  • Daly, Mark J
  • Zwick, Michael E
  • Kugathasan, Subra
  • et al.
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.

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