RT Journal Article
SR Electronic
T1 NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in <em>NCF2</em> that results in reduced binding to RAC2
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1028
OP 1035
DO 10.1136/gutjnl-2011-300078
VO 61
IS 7
A1 Muise, Aleixo M
A1 Xu, Wei
A1 Guo, Cong-Hui
A1 Walters, Thomas D
A1 Wolters, Victorien M
A1 Fattouh, Ramzi
A1 Lam, Grace Y
A1 Hu, Pingzhao
A1 Murchie, Ryan
A1 Sherlock, Mary
A1 Gana, Juan Cristóbal
A1 ,
A1 Russell, Richard K
A1 Glogauer, Michael
A1 Duerr, Richard H
A1 Cho, Judy H
A1 Lees, Charlie W
A1 Satsangi, Jack
A1 Wilson, David C
A1 Paterson, Andrew D
A1 Griffiths, Anne M
A1 Silverberg, Mark S
A1 Brumell, John H
YR 2012
UL http://gut.bmj.com/content/61/7/1028.abstract
AB 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 p67phox 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.Conclusion These studies suggest that the rare novel p67phox 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.