Abstract

Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients with Crohn's Disease

Denson LA1, Jurickova I2, Karns R2, Shaw KA3, Cutler DJ3, Okou D4, Dodd A4, Quinn K5, Mondal K4, Aronow BJ6, Haberman Y2, Linn A2, Price A2, Bezold R2, Lake K2, Jackson K2, Walters TD7, Griffiths A7, Baldassano RN8, Noe JD9, Hyams JS10, Crandall WV11, Kirschner BS12, Heyman MB13, Snapper S14, Guthery SL15, Dubinsky MC16, Leleiko NS17, Otley AR18, Xavier RJ19, Stevens C19, Daly MJ19, Zwick ME3, Kugathasan S4. Gastroenterology. 2018 Feb 15. pii: S0016-5085(18)30210-5. doi: 10.1053/j.gastro.2018.02.016. [Epub ahead of print]
 
     

Author information

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, OH, USA. Electronic address: lee.denson@cchmc.org.

2 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, OH, USA.

3 Department of Human Genetics, Emory University, Atlanta, GA, USA.

4 Department of Pediatrics, Emory University, Atlanta, GA, USA.

5 Cancer and Blood Disease Institute, Department of Pediatrics, University of Cincinnati College of Medicine and the Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

6 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

7 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

8 Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

9 Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA.

10 Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.

11 Department of Pediatric Gastroenterology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.

12 Department of Pediatrics, The University of Chicago, Chicago, IL, USA.

13 Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA.

14 Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.

15 Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.

16 Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA.

17 Department of Pediatrics, Hasbro Children's Hospital, Providence, RI, USA.

18 Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.

19 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Abstract

BACKGROUND & AIMS: Individuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's Disease (CD). We tested for associations between mutations in genes encoding NADPH oxidases, neutrophil function, and phenotypes of CD in pediatric patients.

METHODS: We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production.

RESULTS: We identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P=.0008) and stricturing complications (P=.002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P=.0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P=.002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P=.009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and anti-microbial responses.

CONCLUSIONS: We identified missense mutations in genes that encode NADPH oxidases in children with CD; these associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.

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