Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study ...of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared ...them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.
ObjectiveTo determine whether a faecal immunochemical test (FIT) for faecal haemoglobin concentration (f-Hb) can be safely implemented in primary care as a rule-out test for significant bowel disease ...(SBD) (colorectal cancer (CRC), higher risk adenoma (HRA) and inflammatory bowel disease (IBD)) when used as an adjunct to the clinical assessment of new bowel symptoms.DesignSingle-centre prospective cohort study of all patients who attended primary care and submitted a FIT in the first calendar year of the service beginning December 2015. f-Hb was estimated using HM-JACKarc (Kyowa Medex) with a clinical cut-off of ≥10 µg Hb/g faeces. Incident cases of CRC were verified via anonymised record linkage to the Scottish Cancer Registry.Results5422 patients submitted 5660 FIT specimens, of which 5372 were analysed (positivity: 21.9%). 2848 patients were referred immediately to secondary care and three with f-Hb <10 µg/g presented acutely within days with obstructing CRC. 1447 completed colonoscopy in whom overall prevalence of SBD was 20.5% (95 CRC (6.6%), 133 HRA (9.2%) and 68 IBD (4.7%)); 6.6% in patients with f-Hb <10 µg/g vs 32.3% in patients with f-Hb ≥10 µg/g. One CRC was detected at CT colonoscopy. 2521 patients were not immediately referred (95.3% had f-Hb <10 µg/g) of which four (0.2%) later developed CRC. Record linkage identified no additional CRC cases within a follow-up period of 23–35 months.ConclusionIn primary care, measurement of f-Hb, in conjunction with clinical assessment, can safely and objectively determine a patient’s risk of SBD.
Many patients present in primary care with lower bowel symptoms, but significant bowel disease (SBD), comprising colorectal cancer (CRC), advanced adenoma (AA), or inflammatory bowel disease (IBD), ...is uncommon. Quantitative faecal immunochemical tests for haemoglobin (FIT), which examine faecal haemoglobin concentrations (f-Hb), assist in deciding who would benefit from colonoscopy. Incorporation of additional variables in an individual risk-score might improve this approach. We investigated if the published f-Hb, age and sex test score (FAST score) added value.
Data from the first year of routine use of FIT in primary care in one NHS Board in Scotland were examined: f-Hb was estimated using one HM-JACKarc FIT system (Kyowa Medex Co., Ltd., Tokyo, Japan) with a cut-off for positivity ≥10 μg Hb/g faeces. 5660 specimens were received for analysis in the first year. 4072 patients were referred to secondary care: 2881 (70.6%) of these had returned a FIT specimen. Of those referred, 1447 had colonoscopy data as well as the f-Hb result (group A): 2521 patients, also with f-Hb, were not immediately referred (group B). The FAST score was assessed in both groups.
1196 (41.7%) of patients who returned a specimen for FIT analysis had f-Hb ≥10 μg Hb/g faeces. In group A, 252 of 296 (85.1%) with SBD had f-Hb > 10 μg Hb/g faeces, as did 528 of 1151 (45.8%) without SBD. Using a FAST score > 2.12, which gives high clinical sensitivity for CRC, only 1143 would have been referred for colonoscopy (21.0% reduction in demand): 286 of 296 (96.6%) with SBD had a positive FAST score, as did 857 of 1151 (74.5%) without SBD. However, one CRC, five AA and four IBD would have been missed. In group B, although 95.2% had f-Hb < 10 μg Hb/g faeces, 1371 (53.7%) had FAST score ≥ 2.12: clinical rationale led to only 122 of group B completing subsequent bowel investigations: a FAST score > 2.12 was found in 13 of 15 (86.7%) with SBD.
The performance characteristics of the FAST score did not seem to enhance the utility of f-Hb alone. Locally-derived formulae might confer desired benefits.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims:
The
MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The
MDR1 exonic single nucleotide polymorphisms (SNPs) ...C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170.
Methods:
This was a case-control analysis of
MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis UC, 268 with Crohn’s disease CD, and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses.
Results:
The
MDR1 3435 TT genotype (34.6% vs 26.5%;
P = .04; odds ratio OR, 1.60; 95% confidence interval 95% CI, 1.04–2.44) and T-allelic frequencies (58.2% vs 52.8%;
P = .02; OR, 1.28; 95% CI, 1.03–1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%;
P = .003; OR, 2.64; 95% CI, 1.34–4.99; and T allele: 63.9% vs 52.8%;
P = .009; OR, 1.70; 95% CI, 1.24–2.29), and this was also confirmed on multivariate analysis (
P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D′, .8–.9;
r
2, .7–.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype:
P = .03; OR, 1.44) and negative (C3435/2677T haplotype:
P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC (
P = .017; OR, 8.88; 95% CI, 1.10–71.45).
Conclusions:
Allelic variations of the
MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.
Background & Aims: Omeprazole produces greater acid inhibition in Helicobacter pylori–positive than –negative subjects. We investigated whether this is accompanied by more profound changes in the ...intragastric milieu that facilitates bacterial synthesis of N-nitroso compounds. Methods: Gastric juice pH; nitrite, ascorbic acid, and total vitamin C concentrations; and colonization by other bacteria were examined before and during omeprazole treatment in subjects with and without H. pylori infection. Studies were performed in the fasting state and after consumption of 2 mmol nitrate (equivalent to a salad meal). Results: Before omeprazole, H. pylori–positive and –negative subjects were similar for all parameters. During omeprazole, H. pylori–positive subjects had a higher intragastric pH (7.8 vs. 3.0; P < 0.00001) and greater colonization with non–H. pylori species (5 × 107 vs. 5 × 105 CFU/mL; P < 0.05). These bacteria included nitrosating species. During omeprazole treatment, H. pylori–positive subjects had higher intragastric nitrite levels after the nitrate meal (median area under the concentration/time curve, 12,450 vs. 4708 μmol/L · min; P = 0.04). Omeprazole lowered intragastric vitamin C levels in H. pylori–positive but not –negative subjects (1.8 vs. 3.4 μg/mL, respectively; P = 0.02). Conclusions: In H. pylori–positive subjects, omeprazole produces disturbances in intragastric nitrite, vitamin C, and bacterial colonization that facilitate bacterial N-nitrosation. This may place them at increased risk of mutagenesis and carcinogenesis.
GASTROENTEROLOGY 2000;119:339-347
Background
Difficulties in establishing diagnosis of small bowel (SB) disorders, prevented their effective treatment. This problem was largely resolved by wireless capsule endoscopy (WCE), which has ...since become the first line investigation for suspected SB disorders. Several types of WCE pills are now used in clinical practice, despite their limitations and complications. WCE pills are large, rigid and immotile capsules. When swallowed, they provide SB enteroscopy downloaded to a data logger carried by the patient. Most of the complications of WCEs result from lack of intrinsic locomotion: incomplete examination, capsule retention and impaction within strictures. In addition, the rigid nature and size of current generation of WCE pills is accompanied by 0.1% inability to swallow the pill by patients with normal esophageal motility.
Methods
The aim of this communication is to describe the initial prototype, P
1
, which is thinner and slightly longer than the current generation of WCEs. In addition, it exhibits intrinsic active locomotion, produced by vibrating silicon legs. These generate a controlled-skid locomotion on the small bowel mucosal surface, rendered slippery by surface mucus and intraluminal surfactant bile salts. We demonstrate the mechanism responsible for the active locomotion of P
1
, which we consider translatable into a working prototype, suitable for further R&D for eventual clinical translation.
Results
The shape and attachment of the rubber vibrating legs to vibrating actuators, have been designed specifically to produce a tight clockwise circular motion. When inserted inside a circular tube in vitro of equivalent diameter to human small intestine, the intrinsic circular clockwise motion of P
1
translates into a linear locomotion by the constraints imposed by the surrounding circular walls of SB and rest of the gastrointestinal tract. This design ensures device stability during transit, essential for imaging and targeting lesions encountered during the enteroscopy. We preformed two experiments: (i) transit of P
1
through a phantom consisting of a segment of PVC tube placed on a horizontal surface and (ii) transit through a transparent slippery nylon sleeve insufflated with air. In the PVC tube, its transit rate averages 15.6 mm/s, which is too fast for endoscopy: whereas inside the very slippery nylon sleeve insufflated with air, the average transit rate of P
1
is reduced to 5.9 mm/s, i.e., ideal for inspection endoscopy.
Conclusions
These in-vitro experiments indicate that the P
1
hybrid soft robot prototype has the potential specifically for clinical translation for SB enteroscopy.
The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in ...management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).
Background
Crohn’s disease (CD) is a chronic, relapsing, inflammatory bowel disease. Up to 65% of patients with CD require an operation to control the disease within 10 years. Both endoscopic and ...clinical recurrence is common within 2 years of operation, with re-operation rates cumulating at 5% of patients per year.
Objectives
This study assessed if the use of mercaptopurine (MP) can prevent or delay postoperative recurrence in CD.
Design
An individually randomised, multicentre, double-blind, placebo-controlled trial with follow-up at 6, 13, 31, 49, 67, 85, 103, 121, 139 and 157 weeks.
Setting
Twenty-nine tertiary referral hospitals in the UK.
Participants
Those aged ≥ 16 years in Scotland (or aged ≥ 18 years in England and Wales) with a histologically confirmed diagnosis of CD (according to the Lennard-Jones criteria) and surgical intervention ≤ 3 months prior to randomisation to remove all observable disease at ileocolonic or small bowel resections. Patients were excluded if they had a known intolerance of or hypersensitivity to thiopurines; were known to require further surgery; underwent strictureplasty alone; had a stoma; or had an active or untreated malignancy or absent thiopurine
S
-methyltransferase (TPMT) activity. Prior to randomisation any postoperative infections were fully treated and existing treatments for CD were stopped.
Intervention
Daily oral dose of MP or placebo, with dose adjusted according to body weight (kg) and TPMT status. Blood samples for genetic and serological analysis were taken at randomisation with additional blood and stool samples collected at weeks 0, 13, 49, 103 and 157 for central analysis of drug metabolite and faecal calprotectin levels, with endoscopic assessment at weeks 49 and 157.
Main outcome measures
The primary end point was clinical recurrence of CD (Crohn’s Disease Activity Index score of > 150 points plus 100-point rise) and the need for anti-inflammatory rescue therapy or primary surgical intervention. Secondary end points included faecal calprotectin and thioguanine levels, and assessment of endoscopic recurrence. The primary analysis was adjusted for baseline values of previous treatment with MP and azathioprine, with the adjusted analysis considered to be the primary analysis.
Results
Between June 2008 and April 2012, 240 patients were enrolled and received at least one dose of the study drug. A total of 128 (53%) participants were randomised to receive MP and 112 (47%) to receive placebo. No randomised patients were excluded from the analysis. More patients achieved the primary end point in the placebo group (
n
= 26, 23.2%) than in the MP group (
n
= 16, 12.5%), with an adjusted
p
-value of 0.073 hazard ratio (HR) 0.535, 95% confidence interval (CI) 0.27 to 1.06. Of the smokers on MP, 3 out of 29 (10.3%) had clinical recurrence versus 12 out of 26 (46.2%) on placebo, demonstrating that MP was effective at preventing postoperative recurrence in smokers (HR 0.127, 95% CI 0.04 to 0.46) but not in non-smokers (HR 0.898, 95% CI 0.42 to 1.94). The proportion of patients experiencing adverse events was similar in the treatment and placebo groups.
Limitations
There was a lower than anticipated primary event rate (12.5% in the treatment group vs. 23.2% in the placebo group, as opposed to expected rates of 30% vs. 50%).
Conclusions
The Trial Of Prevention of Post operative Crohn’s disease (TOPPIC) is the largest single, double-blind trial assessing the use of thiopurines to prevent postoperative recurrence in CD. From the trial itself, MP was not effective in reducing the frequency of clinical postoperative recurrence of CD overall, but the data suggest that it has clinically meaningful effect among the subgroup of patients who continue to smoke after surgery.
Future work
Exploratory analyses of possible predictors of disease recurrence using collected data and samples.
Trial registration
Current Controlled Trials ISRCTN89489788 and EudraCT 2006-005800-15.
Funding
This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in
Efficacy and Mechanism Evaluation
; Vol. 4, No. 4. See the NIHR Journals Library website for further project information.
In primary care, assessing which patients with bowel symptoms harbour significant disease (cancer, higher-risk adenoma or IBD) is difficult. We studied the diagnostic accuracies of faecal haemoglobin ...(FHb) and faecal calprotectin (FC) in a cohort of symptomatic patients.
From October 2013 to March 2014, general practitioners were prompted to request FHb and FC when referring patients with bowel symptoms to secondary care. Faecal samples were analysed for haemoglobin (EIKEN OC-Sensor io) and calprotectin (BÜHLMANN Calprotectin ELISA). Patients triaged to endoscopy were investigated within 6 weeks. All clinicians and endoscopists were blind to the faecal test results. The diagnostic accuracies of FHb and FC for identification of significant bowel disease were assessed.
1043 patients returned samples. FHb was detectable in 57.6% (median 0.4 µg/g, 95% CI 0.4 to 0.8; range 0-200). FC at 50 µg/g or above was present in 60.0%. 755 patients (54.6% women, median age 64 years (range 16-90, IQR 52-73)) returned samples and completed colonic investigations. 103 patients had significant bowel disease; the negative predictive values of FHb for colorectal cancer, higher-risk adenoma and IBD were 100%, 97.8% and 98.4%, respectively. Using cut-offs of detectable FHb and/or 200 µg/g FC detected two further cases of IBD, one higher-risk adenoma and no additional cancers.
In primary care, undetectable FHb is a good 'rule-out' test for significant bowel disease and could guide who requires investigation.
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