Anne Phillips

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohns disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10−8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohns disease.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 × 10−5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10−17), 16q22 (CDH1 and CDH3; P = 2.8 × 10−8) and 7q31 (LAMB1; P = 3.0 × 10−8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

Detailed Haplotype- Tagging Study of Germline Variation of MUC19 in Inflammatory Bowel Disease

To the Editor:Since the discovery of NOD2 as aCrohn’s disease (CD) susceptibilitygene, more recent genomewide associa-tion scans (GWAS), detecting loci con-ferring odds ratios (OR) of above 1.3–1.5, have uncovered a large number offurther susceptibility loci and genes,including IL23R in the TH17 pathway,and the autophagy genes ATG16L1 andIRGM.

Clinical and genetic factors predict severe disease: a novel composite severity index

Introduction Crohns disease is an incurable progressive disease with marked heterogeneity in outcome. Identifying patients at diagnosis (Dx) at high risk of poor outcomes would allow treatment stratification. Current definitions of severe disease lack discrimination. A more discriminant composite severity score would benefit clinical research and aid clinical decision making. Methods Based on a consensus of 5 clinicians, the authors designed a composite severity score, assessed over the 5 years after Dx, with a total possible score 1–16. The score was applied retrospectively in 367 CD patients who were also genotyped for 32 CD susceptibility loci. The severity score that would encompass the 50% of patients with the highest score was defined, and factors present at Dx – both clinical and genetic – were assessed by the χ2 test for their ability to predict being in the more severe disease category. CD was classified according to the Montreal classification. Results 367 CD patients (median age at Dx 30.8 (IQR 22.9–46.1)) were assessed. 249 patients had full data available for the first 5 years after Dx. The mean severity score was 6.3 (95% CI 5.9 to 6.6). Patients with a score >6 were defined as having more severe disease. Patients with more severe disease were younger at Dx (p=0.0004 for trend, OR A1 vs A2=4.42 (95% CI 1.4 to 13.9)) and had an ileal (p=0.0025, OR=2.2 (95% CI 1.32 to 3.68)) and upper GI location disease location at Dx (p=0.0008, OR=5.3 95% CI 1.9 to 14.7). Perianal disease at Dx approached but did not achieve statistical significance (p=0.052). Only rs9286879 (p=0.0085) and rs17582416 (p=0.0448) were observed more frequently in patients with severe disease. The need for steroids at Dx, having a first degree relative with IBD, needing surgery at Dx or smoking status at Dx did not differ between the groups. Conclusion This index discriminates more effectively between severity groups. Disease location, age at Dx and genetic markers are associated with more severe disease but validation of these factors is needed in a separate cohort.

Surgery in Crohn's Disease: Analysis of 15000 Patient-Years Experience in Eastern Scotland

G A A b st ra ct s clinical depression was not significant. Using corticosteroids was associated with less fatigue (OR 0.12; 95% CI 0.03-0.52). The different hospitals settings (academic vs general), age and other medication use were not associated with higher fatigue scores. In group B, 545 pts were included (64% female, 77.4% CD, 22.6% UC, mean age 42 (SD 14)) and this group verified the results of group A. However, overall only 60% experienced fatigue and mean CIS score was lower (mean 37 (range 8-56) compared with group A. Furthermore, the use of anti-TNF and male gender were associated with lower percentage of fatigue in CD pts. Conclusion: A high percentage of IBD pts experience severe fatigue. Depression and disease activity were associated with fatigue in these patients. The use of anti-TNF and male gender in CD pts showed the opposite effect and were associated with less fatigue. In UC pts the use of corticosteroids showed less fatigue.