title: NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2.
abstract: OBJECTIVE
  The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD).
  
  
  METHODS
  Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts.
  
  
  RESULTS
  Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10(-5), OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67(phox) to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD.
  
  
  CONCLUSIONS
  These studies suggest that the rare novel p67(phox) variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca
authors: Aleixo M
authors: AM
authors: Muise
authors: Wei
authors: W
authors: Xu
authors: Cong-Hui
authors: CH
authors: Guo
authors: Thomas D
authors: TD
authors: Walters
authors: Victorien M
authors: VM
authors: Wolters
authors: Ramzi
authors: R
authors: Fattouh
authors: Grace Y
authors: GY
authors: Lam
authors: Pingzhao
authors: P
authors: Hu
authors: Ryan
authors: R
authors: Murchie
authors: Mary
authors: M
authors: Sherlock
authors: Juan Cristóbal
authors: JC
authors: Gana
authors: Richard K
authors: RK
authors: Russell
authors: Michael
authors: M
authors: Glogauer
authors: Richard H
authors: RH
authors: Duerr
authors: Judy H
authors: JH
authors: Cho
authors: Charlie W
authors: CW
authors: Lees
authors: Jack
authors: J
authors: Satsangi
authors: David C
authors: DC
authors: Wilson
authors: Andrew D
authors: AD
authors: Paterson
authors: Anne M
authors: AM
authors: Griffiths
authors: Mark S
authors: MS
authors: Silverberg
authors: John H
authors: JH
authors: Brumell
mesh_terms: D003424:Crohn Disease / Q000235:genetics*; D060005:Genotyping Techniques; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D020744:rac GTP-Binding Proteins / Q000235:genetics*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C527764:NCF2 protein, human