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Published on: September 22, 2019
Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very
Sandeep S Dhillon1, Ramzi Fattouh2, Abdul Elkadri3
1SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Insights
Very early onset inflammatory bowel disease (VEOIBD) is linked to specific genetic variants in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. These variants do not cause immunodeficiency but increase susceptibility to VEOIBD.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- Colitis in very early onset inflammatory bowel disease (VEOIBD) resembles chronic granulomatous disease (CGD).
- CGD results from defects in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex genes.
- Investigating NADPH oxidase gene variants in VEOIBD susceptibility.
Purpose of the Study:
- To determine if variants in NADPH oxidase genes contribute to VEOIBD susceptibility.
- To analyze the functional impact of identified gene variants.
Main Methods:
- Targeted exome sequencing of NADPH oxidase component genes in 122 VEOIBD patients.
- Validation of variants in an independent cohort.
- Examination of single nucleotide polymorphisms (SNPs) in NOX2 NADPH oxidase genes.
- Functional analysis of associated variants.
Main Results:
- Eleven variants associated with VEOIBD were identified, mostly in heterozygous form.
- Variants reduced oxidative burst or altered NADPH oxidase protein interactions.
- Noncoding variants led to reduced protein levels or altered protein forms in VEOIBD patients' blood cells.
Conclusions:
- VEOIBD patients carry heterozygous, functional hypomorphic variants in NOX2 NADPH oxidase complex components.
- These variants confer susceptibility to VEOIBD without causing overt immunodeficiency.
- Potential for developing targeted VEOIBD treatments based on specific genetic variants.
Background & Aims:
The colitis observed in patients with very early onset inflammatory bowel disease (VEOIBD; defined as onset of disease at younger than 6 years of age) often resembles that of chronic granulomatous disease (CGD) in extent and features of colonic inflammation observed by endoscopy and histology. CGD is a severe immunodeficiency caused by defects in the genes that encode components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. We investigated whether variants in genes that encode NADPH oxidase components affect susceptibility to VEOIBD using independent approaches.
Methods:
We performed targeted exome sequencing of genes that encode components of NADPH oxidases (cytochrome b light chain and encodes p22(phox) protein; cytochrome b-245 or NADPH oxidase 2, and encodes Nox2 or gp91(phox); neutrophil cytosol factor 1 and encodes p47 (phox) protein; neutrophil cytosol factor 2 and encodes p67 (phox) protein; neutrophil cytosol factor 4 and encodes p40 (phox) protein; and Ras-related C3 botulinum toxin substrate 1 and 2) in 122 patients with VEOIBD diagnosed at The Hospital for Sick Children, University of Toronto, from 1994 through 2012. Gene variants were validated in an independent International Early Onset Pediatric IBD Cohort Study cohort of patients with VEOIBD. In a second approach, we examined Tag single nucleotide polymorphisms in a subset of patients with VEOIBD in which the NOX2 NADPH oxidase genes sequence had been previously analyzed. We then looked for single nucleotide polymorphisms associated with the disease in an independent International Early Onset Pediatric IBD Cohort Study cohort of patients. We analyzed the functional effects of variants associated with VEOIBD.
Results:
Targeted exome sequencing and Tag single nucleotide polymorphism genotyping identified 11 variants associated with VEOIBD; the majority of patients were heterozygous for these variants. Expression of these variants in cells either reduced oxidative burst or altered interactions among proteins in the NADPH oxidase complex. Variants in the noncoding regulatory and splicing elements resulted in reduced levels of proteins, or expression of altered forms of the proteins, in blood cells from VEOIBD patients.
Conclusions:
We found that VEOIBD patients carry heterozygous functional hypomorphic variants in components of the NOX2 NADPH oxidase complex. These do not cause overt immunodeficiency, but instead determine susceptibility to VEOIBD. Specific approaches might be developed to treat individual patients based on their genetic variant.
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