- Fecal Incontinence
|Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease
Denson LA1, Jurickova I1, Karns R1, Shaw KA2, Cutler DJ2, Okou D3, Alexander Valencia C4, Dodd A3, Mondal K3, Aronow BJ5, Haberman Y1, Linn A1, Price A1, Bezold R1, Lake K1, Jackson K1, Walters TD6, Griffiths A6, Baldassano RN7, Noe JD8, Hyams JS9, Crandall WV10, Kirschner BS11, Heyman MB12, Snapper S13, Guthery SL14, Dubinsky MC15, Leleiko NS16, Otley AR17, Xavier RJ18, Stevens C18, Daly MJ18, Zwick ME2, Kugathasan S3. Inflamm Bowel Dis. 2018 Aug 13. doi: 10.1093/ibd/izy265. [Epub ahead of print]
1 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Cincinnati College of Medicine and the Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
2 Department of Human Genetics, Emory University, Atlanta, Georgia.
3 Department of Pediatrics, Emory University, Atlanta, Georgia.
4 Program and Division of Human Genetics, Molecular Genetics Laboratory, Cincinnati, Ohio.
5 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
6 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
7 Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
8 Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin.
9 Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut.
10 Department of Pediatric Gastroenterology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio.
11 Department of Pediatrics, The University of Chicago, Chicago, Illinois.
12 Department of Pediatrics, University of California at San Francisco, San Francisco, California.
13 Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts.
14 Department of Pediatrics, University of Utah, Salt Lake City, Utah.
15 Department of Pediatrics, Mount Sinai Hospital, New York, New York.
16 Department of Pediatrics, Hasbro Children's Hospital, Providence, Rhode Island.
17 Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
18 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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 diseaseneutrophils 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.