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Background Serious infections have been observed in patients with inflammatory bowel disease (IBD) on anti-TNF use—but to what extent these infections are due to anti-TNF or the disease activity per se is hard to disentangle. We aimed to describe how the rates of serious infections change over time both before and after starting anti-TNF in IBD. Methods Inflammatory bowel disease patients naïve to anti-TNF treatment were identified at 5 centers participating in the Swedish IBD Quality Register, and their medical records examined in detail. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated. Results Among 980 patients who started their first anti-TNF therapy between 1999 and 2016, the incidence rate of serious infections was 2.19 (95% CI,1.43-3.36) per 100 person years the year before and 2.11 (95% CI, 1.33-3.34) per 100 person years 1 year after treatment start. This corresponded to an incidence rate ratio 1 year after anti-TNF treatment of 0.97 (95% CI, 0.51-1.84). Compared with before anti-TNF therapy, the incidence of serious infection was significantly decreased more than 1 year after treatment (incidence rate ratio 0.56; 95% CI, 0.33-0.95; P = .03). Conclusions In routine clinical practice in Sweden, the incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.

Background Prospectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce. Aims To assess the long-term effectiveness of ustekinumab in patients with active Crohns disease (CD). Methods This is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey-Bradshaw Index (HBI) = 3-point-decrease in HBI among patients with initial HBI >= 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures. Results Of 114 included patients, 107 (94%) had previously failed >= 1 and 58 (51%) >= 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed. Conclusions In this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care. Funding Agencies|Karolinska InstituteKarolinska Institutet; Janssen Cilag AB, Sweden

Supplemental material, sj-docx-1-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-3-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-3-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable bowel syndrome (IBS) results from disordered brain���gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain���gut interactions underlying IBS.

Additional file 1: eTable 1. ICD-7 codes for cancer outcomes. eTable 2. Definitions of endoscopy, colectomy, and proctocolectomy. eTable 3. Incidence rate of cancer in individuals with a GI biopsy result of normal mucosa and their matched population references. eTable 4. Average risk of any cancer during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 5. Risk of specific cancers during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 6. Cumulative incidence and its difference of specific cancers during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 7. Sensitivity analyses for the risk of any cancer during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 8. Characteristics of individuals with a gastrointestinal (GI) biopsy result of normal mucosa and their siblings, a nationwide matched cohort study in Sweden, 1965-2016. eTable 9. Association between a GI biopsy result of normal mucosa and risk of any cancer, starting follow-up from 6 months vs. 1 year after biopsy. eFigure 1. Standardized cumulative incidence and 95% confidence intervals of any cancer in individuals with a GI biopsy result of normal mucosa (solid line and orange) and their matched references (dotted line and blue), stratified by age at cohort entry or calendar period of cohort entry. Follow-up was started 6 months after the biopsy. eFigure 2. Hazard ratio (HR) and 95% confidence intervals (CIs) of any cancer as a function of time since biopsy, comparing individuals with a GI biopsy result of normal mucosa with their matched references, stratified by calendar period of cohort entry. eFigure 3. Standardized cumulative incidence and 95% confidence intervals of specific cancers in individuals with a GI biopsy result of normal mucosa (solid line and orange) and their matched references (dotted line and blue). Follow-up was started 6 months after the biopsy. eFigure 4. Average hazard ratio (HR) and 95% confidence intervals (CIs) of specific cancers, comparing individuals with a GI biopsy result of normal mucosa with their matched references, stratified by biopsy location: upper (blue) or lower (orange) GI. Follow-up was started 6 months after the biopsy. eFigure 5. (A). Hazard ratio (HR) and 95% confidence intervals (CIs) of any cancer, comparing individuals with a GI biopsy result of normal mucosa with their siblings; (B). Standardized cumulative incidence and 95% confidence intervals of any cancer in individuals with normal mucosa (solid line and orange) and their siblings (dotted line and blue). Both were estimated from the flexible parametric model and follow-up was started 6 months after the biopsy.

Supplemental material, sj-docx-2-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

To investigate absolute and relative risk of serious infections in adult/elderly inflammatory bowel disease (IBD) diagnosed 2002–2017. Nationwide, register-based cohort study of Swedish patients with IBD compared with general population matched reference individuals with regard to time to first serious infection, equal to hospital admission. Multivariable Cox regression estimated hazard ratios (HRs) for any serious infection. Secondary outcomes included site-specific infections, opportunistic infections and sepsis. We identified 47 798 individuals with IBD. During a follow-up of 329 000 person-years, they had 8752 first serious infections (26.6 per 1000 person-years). This compared with an incidence rate of 10.7 per 1000 person-years in matched reference individuals, corresponding to a 2.53-fold increased hazard of serious infections (95%CI = 2.47–2.59). The HR for serious infection in elderly-onset IBD was 2.01 (95%CI = 1.95–2.08). The relative hazard of serious infection was somewhat higher in Crohn’s disease (2.94; 95%CI = 2.81–3.06) than in ulcerative colitis (2.24; 95%CI = 2.17–2.31). The HR for serious infections was high in the first year of follow-up (5.17; 95%CI = 4.93–5.42). Individuals with IBD were at a particularly high relative hazard of gastrointestinal and opportunistic infections. The HR for sepsis was 2.47 (95%CI = 2.32–2.63). The relative rates for serious infections in IBD increased in recent years. Patients with adult-onset IBD are at increased risk of serious infections, particularly gastrointestinal and opportunistic infections. Relative rates were highest just after IBD diagnosis, and seem to have increased in recent years.

Some studies have suggested a reduced life expectancy in patients with Crohn���s disease (CD) compared with the general population. The evidence, however, is inconsistent. Prompted by such studies, we studied survival of CD patients in ��rebro county, Sweden. From the medical records, we identified all patients diagnosed with CD during 1963���2010 with follow-up to the end of 2011. We estimated: overall survival, net and crude probabilities of dying from CD, relative survival ratio (RSR), and excess mortality rate ratios (EMRR) at 10-year follow-up. The study included 492 patients (226 males, 266 females). Median age at diagnosis was 32 years (3���87). Net and crude probabilities of dying from CD increased with increasing age and were higher for women. Net survival of patients aged ���60 at diagnosis was worse for patients diagnosed during 1963���1985 (54%) than for patients diagnosed during 1986���1999 (88%) or 2000���2010 (93%). Overall, CD patients��� survival was comparable to that in the general population [RSR = 0.98; 95% CI: (0.95���1.00)]. However, significantly lower than expected survival was suggested for female patients aged ���60 diagnosed during the 1963���1985 [RSR = 0.47 (0.07���0.95)]. The adjusted model suggested that, compared with diagnostic period 1963���1985, disease-related excess mortality declined during 2000���2010 [EMRR = 0.36 (0.07���1.96)]; and age ���60 at diagnosis [EMRR = 7.99 (1.64���39.00), reference: age 40���59], female sex [EMRR = 4.16 (0.62���27.85)], colonic localization [EMRR = 4.20 (0.81���21.88), reference: ileal localization], and stricturing/penetrating disease [EMRR = 2.56 (0.52���12.58), reference: inflammatory disease behaviour] were associated with poorer survival. CD-related excess mortality may vary with diagnostic period, age, sex and disease phenotype.Key summaryThere is inconsistent evidence on life expectancy of patients with Crohn���s diseaseCrohn���s disease-specific survival improved over time.Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn���s disease-related mortality. There is inconsistent evidence on life expectancy of patients with Crohn���s disease Crohn���s disease-specific survival improved over time. Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn���s disease-related mortality.

Supplemental material, sj-docx-1-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

Supplemental material, sj-pdf-1-ueg-10.1177_2050640620945949 for The use of 5-aminosalicylate for patients with Crohn’s disease in a prospective European inception cohort with 5 years follow-up – an Epi-IBD study by Johan Burisch, Daniel Bergemalm, Jonas Halfvarson, Viktor Domislovic, Zeljko Krznaric, Adrian Goldis, Jens F Dahlerup, Pia Oksanen, Pekka Collin, Luisa de Castro, Vicent Hernandez, Svetlana Turcan, Elena Belousova, Renata D'Incà, Alessandro Sartini, Daniela Valpiani, Martina Giannotta, Ravi Misra, Naila Arebi, Dana Duricova, Martin Bortlik, Kelly Gatt, Pierre Ellul, Natalia Pedersen, Jens Kjeldsen, Karina W Andersen, Vibeke Andersen, Konstantinos H Katsanos, Dimitrios K Christodoulou, Shaji Sebastian, Luisa Barros, Fernando Magro, Jóngerð MM Midjord, Kári R Nielsen, Riina Salupere, Hendrika AL Kievit, Gediminas Kiudelis, Juozas Kupčinskas, Mathurin Fumery, Corinne Gower-Rousseau, Ioannis P Kaimakliotis, Doron Schwartz, Selwyn Odes, Laszlo Lakatos, Peter L Lakatos, Ebbe Langholz, Pia Munkholm and for the Epi-IBD group in United European Gastroenterology Journal

Supplemental material, sj-pdf-1-ueg-10.1177_2050640620945949 for The use of 5-aminosalicylate for patients with Crohn’s disease in a prospective European inception cohort with 5 years follow-up – an Epi-IBD study by Johan Burisch, Daniel Bergemalm, Jonas Halfvarson, Viktor Domislovic, Zeljko Krznaric, Adrian Goldis, Jens F Dahlerup, Pia Oksanen, Pekka Collin, Luisa de Castro, Vicent Hernandez, Svetlana Turcan, Elena Belousova, Renata D'Incà, Alessandro Sartini, Daniela Valpiani, Martina Giannotta, Ravi Misra, Naila Arebi, Dana Duricova, Martin Bortlik, Kelly Gatt, Pierre Ellul, Natalia Pedersen, Jens Kjeldsen, Karina W Andersen, Vibeke Andersen, Konstantinos H Katsanos, Dimitrios K Christodoulou, Shaji Sebastian, Luisa Barros, Fernando Magro, Jóngerð MM Midjord, Kári R Nielsen, Riina Salupere, Hendrika AL Kievit, Gediminas Kiudelis, Juozas Kupčinskas, Mathurin Fumery, Corinne Gower-Rousseau, Ioannis P Kaimakliotis, Doron Schwartz, Selwyn Odes, Laszlo Lakatos, Peter L Lakatos, Ebbe Langholz, Pia Munkholm and for the Epi-IBD group in United European Gastroenterology Journal

Background We aimed to describe the long-term impact of achieving endoscopic and deep remission among participants in the effect of tight control management on CD (CALM) trial. Methods We analysed medical records from patients with follow-up data since end of CALM. Patients were stratified by outcomes in CALM at 1 year: clinical remission (Crohn’s disease activity index, CDAI Results One hundred twenty-two patients with median age 29 years (IQR 22.5–37) and median disease duration 0.2 years (IQR 0.1–0.8) were included. Median follow-up time from end of CALM was 3.02 years (range 0.05–6.26 years). Fifty per cent were randomised to the tight control arm. There were no significant differences in baseline characteristics in patients with follow-up data and those lost to follow-up with the exception of a slightly higher CDEIS score in patients lost to follow-up (14.6 vs. 12.9, p = 0.04). Thirty-four patients (27.9%) had a major adverse outcome during follow-up. Patients in clinical remission at 1 year did not have significantly lower rates of the composite endpoint (log-rank p = 0.15). Patients in endoscopic and deep remission at the end of CALM were significantly less likely to have a major adverse event over time (Figures 1 and 2). After adjusting for age, disease duration, prior surgery, prior stricture, and randomisation arm, endoscopic remission (aHR 0.44, 95% CI 0.20–0.96, p = 0.038) and deep remission (aHR 0.25, 95% CI 0.09–0.72, p = 0.01) were significantly associated with lower risk of major adverse events. Conclusions Early CD patients who achieve endoscopic or deep remission after 1 year of intensive treatment are less likely to have disease progression over a median of 3 years.

Additional file 1: Table S1. IBD-related surgical procedure codes included in the review process with frequency of validated codes; 2) Table S2. Classification and definitions of coding errors in the NPR with frequency Table S1 includes all surgical procedure codes included in the review process with frequency of validated codes. Table S2 shows the classification and definitions of coding errors used in the validation process together with frequency of identified errors.

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

Background & aimsGenome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.MethodsWe sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.ResultsWe identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.ConclusionsWe have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. Aim was to construct and validate a web-based inception cohort database available in both English and Russian language. The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

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.