The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.
Abstract: We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system. One Sentence Summary: We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.
To evaluate clinical outcomes, patterns of use, tolerance and nutritional outcomes of exclusive enteral nutrition (EEN) in adults with Crohn's disease and to compare initiation in the inpatient compared with ambulatory care setting.Adults with Crohn's disease who received EEN at a single centre over 2.5 years were identified and outcomes assessed via examination of patient records.EEN was initiated in 60 patients (23 as an outpatient) who had objective evidence of active disease. Of 49 in whom the goal was induction of remission, 28 completed EEN and 24 achieved clinical remission/response. Twenty-one withdrew prematurely, due to intolerance in 15 and disease factors in 6. Of 11 with a planned intervention, 6 fulfilled the goal of downstaging disease while two were intolerant. Completion of the prescribed therapy was associated with self-reported adherence to EEN and with improvements in disease activity scores and biochemical markers. Malnutrition halved (40% to 20%) and intentional weight loss (median 5.1 kg) was achieved in six obese patients. The major reason for intolerance was the inability to accept total avoidance of non-formula food. There were no differences in any outcomes according to the location of initiation of therapy.Positive outcomes occur in 70% of adult patients with Crohn's disease tolerating EEN and 81% in those who are able to completely adhere to EEN, without compromise of nutritional status. Similar success occurs when initiated as an inpatient or outpatient. Failure to tolerate EEN is the major hurdle to its use.
ABSTRACT Background Advice to avoid dietary emulsifiers in Crohn's disease (CD) is based on preclinical data. Aims To examine the effect of diets high (HED) and low (LED) in emulsifiers in the food supply on disease activity in CD. Methods In a double‐blinded, randomised feeding study, we randomised adults with symptomatic, sonographically active CD with ileal involvement on ≥ 2 months' stable medical therapy to 4 weeks of a HED or LED modelled on Australian healthy eating guidelines. We measured the Harvey‐Bradshaw Index (HBI), sonographic indices (IBUS‐SAS, bowel wall thickness), quality of life (QOL) and fatigue at baseline and study completion. Results We randomised 24 patients, mean age 37 (95% CI 32, 41) years, 12 male, HBI 6 (6, 8), bowel wall thickness 6.0 (5.5–6.6) mm. Adherence was > 95%. Clinical remission (HBI < 5) occurred in 9/12 on HED and 7/12 on LED; 2 and 3, respectively, withdrew early with increasing gastrointestinal symptoms. IBUS‐SAS fell from 51 (35, 68) to 33 (15, 51) on HED ( p = 0.014) and from 57 (38, 76) to 44 (29, 59) on LED ( p = 0.01). Bowel wall thickness reduced by 34% on HED and 15% on LED in those who completed the study. QOL and fatigue improved on both diets ( p ≤ 0.05). There were no statistically significant differences in outcomes between diets. Conclusions In the context of a healthy diet, the emulsifier content had no influence over disease activity over 4 weeks in patients with CD. Recommendations to avoid emulsifiers in patients with active CD are not supported. Australian New Zealand Clinical Trials Registry (ACTRN12619001099112).
Abstract Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
Background: Secondary loss of response to infliximab (IFX) or adalimumab (ADA) is common in inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) identifies patients with sub-therapeutic drug levels who are more likely to respond to dose intensification. Delivering dose-intensified therapy is resource-intensive and may benefit from a non-conventional decision making system such as a virtual clinic (VC). We sought to determine whether enrolment in a VC following a “treat-to-target” paradigm was effective in controlling disease activity in this complex cohort of patients. Methods: Observational study of 37 IBD patients with secondary loss of response referred to our VC between September 2013-October 2016. Dose-intensification involved shortening the interval between ADA and IFX administration to weekly or six-weekly, respectively. Patients were reviewed in our VC every 6 months with scheduled C-reactive protein (CRP), faecal calprotectin (FC), intestinal ultrasound and IFX/ADA TDM using a drug-sensitive ELISA. Response was defined as maintaining improvements in biomarkers and physician global assessment for ≥12 months after initiation of intensified therapy, including those subsequently de-escalated to standard dosing. Patients failing intensified therapy were defined as non-responders. Receiver-operator characteristic analysis was performed to identify a threshold delta increase in drug level associated with response. Results: 86% had Crohn's disease; 62% were treated with IFX. 22 (59%) responded, 55% of whom received IFX. 11 (30%) responders were de-escalated to standard dosing (median 12 months). 15 (41%) were non-responders (median 9 months). Considering the entire cohort, FC and CRP decreased after 12 months compared to baseline (450 vs. 80μg/g; p=0.019 and 8.5 vs. 3.5mg/L; p=0.004, respectively). Subgroup analyses of biomarker and TDM are shown in Table 1. Increasing IFX drug level >3μg/mL from baseline best predicted response (area under curve 0.86, sensitivity 80, specificity 78%). No threshold was found for ADA. Table 1. Responder vs. non-responder biomarker & drug levels (median; delta = difference between baseline & last test) Conclusions: A novel virtual clinic model to deliver intensified anti-TNF therapy enabled recapture of response in the majority of patients, with almost one-third de-escalated to standard dosing. IFX drug levels increased in responders compared with non-responders and a threshold increase of >3μg/mL from baseline was associated with response. Non-responders treated with ADA showed similar increases in drug level to responders, suggesting that outcome was independent of ADA levels.
Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.
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