An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis

Background and Aims: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. Methods: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [nonMRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. Results: MRUC–control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10−9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10−19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10−6]. No SNPs reached significance in the non-MRUC–control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10−8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. Conclusions: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.Sally Mortlock, Anton Lord, Grant Montgomery, Martha Zakrzewski, Lisa A.Simms, Krupa Krishnaprasad, Katherine Hanigan, James D. Doecke, Alissa Walsh, Ian C. Lawrance, Peter A.Bampton, Jane M. Andrews, Gillian Mahy, Susan J. Connor, Miles P.Sparrow, Sally Bell, Timothy H. Florin, Jakob Begun, Richard B. Gearry, Graham L. Radford-Smit

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Protective role of appendicectomy on onset and severity of ulcerative colitis and Chron's disease

BACKGROUND AND AIMS: Recent studies on appendicectomy rates in ulcerative colitis and Crohn's disease have generally not addressed the effect of appendicectomy on disease characteristics. The aims of this study were to compare appendicectomy rates in Australian inflammatory bowel disease patients and matched controls, and to evaluate the effect of prior appendicectomy on disease characteristics. METHODS: Patients were ascertained from the Brisbane Inflammatory Bowel Disease database. Controls matched for age and sex were randomly selected from the Australian Twin Registry. Disease characteristics included age at diagnosis, disease site, need for immunosuppression, and intestinal resection. RESULTS: The study confirmed the significant negative association between appendicectomy and ulcerative colitis (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.14-0.38; p<0.0001) and found a similar result for Crohn's disease once the bias of appendicectomy at diagnosis was addressed (OR 0.34, 95% CI 0.23-0.51; p<0.0001). Prior appendicectomy delayed age of presentation for both diseases and was statistically significant for Crohn's disease (p=0.02). In ulcerative colitis, patients with prior appendicectomy had clinically milder disease with reduced requirement for immunosuppression (OR 0.15, 95% CI 0.02-1.15; p=0.04) and proctocolectomy (p=0.02). CONCLUSIONS: Compared with patients without prior appendicectomy, appendicectomy before diagnosis delays disease onset in ulcerative colitis and Crohn's disease and gives rise to a milder disease phenotype in ulcerative colitis

Accurate Performance Estimation for Stochastic Marked Graphs by Bottleneck Regrowing ⋆

Abstract. The adequate system performance is usually a critical requirement to be checked during the verification phase of a system. Thus, accurately measuring the performance of current industrial systems, which are often modelled as a Discrete Event Systems (DES), is a need. Due to the state explosion problem, the performance evaluation of DES becomes increasingly difficult as the size of the systems increases. Some approaches, such as the computation of performance bounds, have been developed to overcome this problem. In this paper we propose a new method to produce performance bounds that are sharper than the ones that can be achieved with current methods. The core of our method is an iterative algorithm that initially considers the most constraining bottleneck cycle of the system and adds other cycles to it in each iteration. The proposed method is deeply explained and then applied to a broad set of Marked Graphs.

DOP086 Intestinal resection in Crohn's disease is associated with significant and durable improvement in health related quality of life although to a lesser extent in women and smokers. Results from the POCER study

Background: Health-related QoL (HRQoL) measures perceptions, illness experience, and functional status. Crohn’s disease patients have lower HRQoL, poorer function and more emotional distress than healthy individuals, even when in remission. HRQoL improves with medically or surgically induced remission. We evaluated the effects of surgery on HRQoL. Methods: Mucosal healing was the target in the Post-Operative Crohn’s Endoscopic Recurrence (POCER) treat-to-target study. Drug treatments included metronidazole, and thiopurine or adalimumab for high risk patients (smoker, perforating disease, 2nd operation). Patients were randomised to colonoscopy at 6 months with intensified treatment for endoscopic recurrence (“active care”) or no colonoscopy (“standard care”). All patients were colonoscoped at 18 months. HRQoL was assessed with a general (SF36) and disease-specific (IBDQ) questionnaire pre-operatively and at 6, 12 and 18 months. CRP, CDAI and faecal calprotectin (FC) were measured longitudinally. Results: 174 patients (median age 38, 55% female) were included. HRQoL was poor pre-operatively: median SF36 = 40 (where maximum = 100, Australian normal = 70 90) and IBDQ = 120 (maximum = 224, average score in Australian Crohn’s disease patients=156). For all patients both SF36 and IBDQ improved significantly at 6 months to 78 and 178 respectively, and this was sustained at 12 months (81 and 183) and 18 months (80 and 182 respectively). Females had lower HRQoL than males post-op at 6 (SF36 p = 0.012; IBDQ p = 0.007) and 12 months (SF36 p = 0.001, IBDQ p = 0.006). Smokers had poorer HRQoL compared to non-smokers at both 12 and 18 months: SF36 at 12 month p = 0.002, and IBDQ at 12 and 18 months (p = 0.046, p = 0.047 respectively). Persistent endoscopic remission, thiopurine or adalimumab therapy and treatment step up were not associated with changes in HRQoL. There was a significant inverse correlation between CDAI and both SF-36 and IBDQ at 6, 12 and 18 months. HRQoL did not correlate with endoscopic remission, CRP or FC. Conclusions: Intestinal resection of all macroscopic Crohn’s disease, with a focus on maintaining remission, is associated with significant and sustained improvement in general and disease-specific HRQoL. The lower HRQoL in female patients and smokers may reflect partly their lower QoL in the healthy and IBD populations, but this requires further investigation. A higher clinical disease activity index, but not direct measures of active disease or type of drug therapy, is associated with a lower HRQoL, suggesting that symptoms reflect subjective personal factors and not active mucosal disease or drug effects.E.K. Wright ... J.M. Andrews ... P.A. Bampton ... et al

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis

Background: Crohn's disease recurs in the majority of patients after intestinal resection. Aim: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. Methods: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. Results: A total of 101 patients [50% male; median (IQR) age 36 (25–46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2–i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). Conclusions: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.P. De Cruz ... J. M. Andrews ... et al