Harbord, M.; Hankin, A.; Day, R.; Bloom, S.L.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA39
Academic Journal
Chronic bowel inflammation is a feature of chronic granulomatous disease, caused by deficiency in components of the neutrophil and macrophage NADPH oxidase. NCF1, which encodes one such component (p47[sup phox]), is found within a region of significant linkage to inflammatory bowel disease (IBD) on chromosome 7. We hypothesised that NCF1 haplo-insufficiency was a susceptibility factor for IBD. We adapted a Genescan method to identify NCF1 heterozygotes, who were expected to have a high p47[sup phox] pseudogene (ψNCF1) to NCF1 ratio (ΔGT:GTGT), in 138 patients with IBD and 37 controls. We were surprised to find an excess of IBD patients with a ΔGT:GTGT ratio of approximately 1:1, which was greater in CD patients (CD 22.4%; control 8.1%; Fisher's exact test p < 0.05, odds ratio 3.3), than in those with ulcerative colitis (UC) (UC 14.1%; p = 0.28). Co-incidentally, it has been shown that a 1:1 ratio occurs following DNA exchange by recombination or conceivably gene conversion between NCF1 and ψNCF1, to produce a gene hybrid (Type II ψNCF1). The presence of Type II ψNCF1 means that the δGT:GTGT ratio cannot be used to assess NCF1 heterozygosity, so we were unable to confirm our original hypothesis. The functional significance of Type II ψNCF1 remained unknown. Therefore, we assessed the effect of the ΔGT:GTGT ratio on cellular migration into an acute inflammatory cantharidin blister. In patients with a ratio < 1.2 (n = 10; 5 CD, 3 normal subjects), there was a significant increase in blister cell number compared to those patients with a ratio > 1.2 (n = 62; 28 CD, 26 normal subjects), comprising 5.6 +/1.5 × 10[sup 6]/mL (mean +/- standard error) and 2.6 +/- 0.4 × 10[sup 6]/ml respectively (Mann-Whitney test p = 0.03). This applied to both neutrophils (p = 0.06) and macrophages (p = 0.19), which were quantified in 46 subjects, including 8 with a ratio < 1.2. It is therefore conceivable that the presence of Type...


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