Faculty Collaboration Database

Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn's Disease. Gastroenterology 2018 Jun;154(8):2097-2110

Date

02/20/2018

Pubmed ID

29454792

Pubmed Central ID

PMC5985211

DOI

10.1053/j.gastro.2018.02.016

Scopus ID

2-s2.0-85047773432 (requires institutional sign-in at Scopus site)   56 Citations

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 reduced nicotinamide adenine dinucleotide phosphate (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 antimicrobial responses.

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

Author List

Denson LA, Jurickova I, Karns R, Shaw KA, Cutler DJ, Okou DT, Dodd A, Quinn K, 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, Professor in the Pediatrics department at Medical College of Wisconsin

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

Adolescent
Alleles
Child
Child, Preschool
Cohort Studies
Crohn Disease
Down-Regulation
Female
Gene Expression Profiling
Glucose
Humans
Infant
Male
Mutation, Missense
NADPH Oxidases
Neutrophils
Phenotype
Reactive Oxygen Species
Sequence Analysis, RNA
Up-Regulation