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

• Published in: Inflammatory bowel diseases 2019-02, Vol.25 (3), p.547-560
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antibodies; Autoantibodies; Case-Control Studies; Child; Child, Preschool; Crohn Disease - genetics; Crohn Disease - metabolism; Crohn Disease - pathology; Cytokine Receptor Common beta Subunit - genetics; Diseases; Female; Follow-Up Studies; Gastrointestinal diseases; Gene expression; Genes; Genetic aspects; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Infant; Macrophage colony stimulating factor; Macrophages; Male; Mutation, Missense; Neutrophils - metabolism; Neutrophils - pathology; Original Clinical; Pediatric diseases; Pediatrics; Prognosis; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; RNA; RNA sequencing; Transcriptome; Wound care; Wound healing; Young Adult
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1093/ibd/izy265

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.