Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC

No Association Between Pseudopolyps and Colorectal Neoplasia in Patients With Inflammatory Bowel Diseases

Background & Aims: Patients with inflammatory bowel diseases who have postinflammatory polyps (PIPs) have an increased risk of colorectal neoplasia (CRN). European guidelines propose that patients with PIPs receive more frequent surveillance colonoscopies, despite limited evidence of this increased risk. We aimed to define the risk of CRN and colectomy in patients with inflammatory bowel diseases and PIPs. Methods: We conducted a multicenter retrospective cohort study of patients with inflammatory bowel diseases who underwent colonoscopic surveillance for CRN, from January 1997 through January 2017, at 5 academic hospitals and 2 large nonacademic hospitals in New York or the Netherlands. Eligible patients had confirmed colonic disease with duration of at least 8 years (or any duration, if they also had primary sclerosing cholangitis) and no history of advanced CRN (high-grade dysplasia or colorectal cancer) or colectomy. The primary outcome was occurrence of advanced CRN according to PIP status; secondary outcomes were occurrence of CRN (inclusive of low-grade dysplasia) and colectomy. Results: Of 1582 eligible patients, 462 (29.2%) had PIPs. PIPs were associated with more severe inflammation (adjusted odds ratio 1.32; 95% confidence interval [CI] 1.13–1.55), greater disease extent (adjusted odds ratio 1.92; 95% CI 1.34–2.74), and lower likelihood of primary sclerosing cholangitis (adjusted odds ratio 0.38; 95% CI 0.26–0.55). During a median follow-up period of 4.8 years, the time until development of advanced CRN did not differ significantly between patients with and those without PIPs. PIPs did not independently increase the risk of advanced CRN (adjusted hazard ratio 1.17; 95% CI 0.59–2.31). The colectomy rate was significantly higher in patients with PIPs (P =.01). Conclusions: In a retrospective analysis of data from 2 large independent surveillance cohorts, PIPs were associated with greater severity and extent of colon inflammation and higher rates of colectomy, but were not associated with development of any degree of CRN. Therefore, intervals for surveillance should not be shortened based solely on the presence of PIPs

A rule for determining risk of colorectal cancer in patients with inflammatory bowel disease

BACKGROUND & AIMS: Surveillance guidelines for inflammatory bowel disease-associated colorectal cancer (IBD-CRC) are based on findings from retrospective studies. We aimed to create and validate a prediction rule to assist clinicians in identifying patients with IBD who are at low and high risk for CRC. METHODS: We performed a retrospective case-control study of 2 cohorts of patients from tertiary care centers (the University Hospital of Leuven, Belgium, and 7 University Medical Centers in The Netherlands). Multivariate Cox regression was used to select independent risk factors for CRC in the Leuven cohort. Based on their regression coefficients (β), we created a rule to predict risk for CRC. In validation studies, the predictive strength was tested by C-statistic analysis and then validated externally in the Dutch cohort. RESULTS: In total, we identified 50 patients with IBD-CRC (cases) and 136 patients with IBD without CRC (controls) in Leuven, and 138 cases and 206 controls in the Dutch cohort. From the Leuven cohort we created the CRC risk prediction rule based on 4 risk factors: IBD-type ulcerative colitis (β = 1.2), primary sclerosing cholangitis (β = 1.1), extent of colonic disease ≥50% (β = 1.1), and postinflammatory polyps (β = 0.8). The prediction rule consisted of a total score for each individual patient calculated from the presence or absence of these 4 risk factors. For example, a score of 13 represented patients who had extensive Crohn's disease without PSC or postinflammatory polyps, who had a 15% likelihood of CRC in the Leuven cohort and a 24% likelihood of CRC in the Dutch cohort. Scores of 0, 13, 23, 27, and 37 represented patients with Crohn's disease, and scores 15, 25, 28, 38, 42, and 52 represented patients with ulcerative colitis. The total score per patient had a C-statistic of 0.75. In the Dutch cohort this score had a C-statistic of 0.67. CONCLUSIONS: Ulcerative colitis, primary sclerosing cholangitis, disease extent ≥50%, and postinflammatory polyps were found to determine risk for CRC in patients with IBD. A surveillance guideline that incorporates the relative weights of these risk profiles would identify patients at risk for CRC more accurately than algorithms in current guidelines

Clinical experience and diagnostic algorithm of vulval Crohn's disease

Item does not contain fulltextBACKGROUND AND AIM: Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature. PATIENTS AND METHODS: Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected. Results : Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor alpha inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy. CONCLUSION: The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor alpha inhibitors are advised to treat this condition

Clinical experience and diagnostic algorithm of vulval Crohn's disease

Background and aim: Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature. Patients and methods: Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected. Results: Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor α inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy. Conclusion: The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor α inhibitors are advised to treat this condition

Long-term Risk of Cancer Following Ileal Pouch-anal Anastomosis for Ulcerative Colitis

Background: The overall risk of cancer following ileal pouch-anal anastomosis [IPAA] is unknown, and pouch cancer surveillance is controversial. We evaluated long-term risk of cancer in a national cohort of patients with ulcerative colitis and IPAA, with emphasis on pouch cancer.Methods: Data on incident cancers were extracted from the national Danish Cancer Registry. Incidence rates for all site-specific cancers were compared between patients with IPAA and a gender- and age-matched comparison cohort from the background population to obtain incidence rate ratios [IRRs].Results: A total of 1723 patients with IPAA, operated for ulcerative colitis in the period 1980-2010, were matched to 8615 individuals from the background population. During a median follow-up of 12.9 years (interquartile range [IQR] 7.7-19.6 years), two pouch cancers [0.12%] were found after 16 and 27 years, respectively. In the population comparison cohort, 38 intestinal cancers [0.45%] were found, of which 35 were colorectal. The risk of hepatobiliary cancer was higher for patients with IPAA {IRR = 13.0 (95% confidence interval [CI]: 3.1-76.1)}, and half of the affected patients had coexisting primary sclerosing cholangitis. The risk of cancer overall following IPAA was identical to that of the comparison cohort: IRR = 1.05 [0.84-1.31].Conclusions: Pouch cancer following IPAA is very rare, questioning the need for general, rather than selective, surveillance. The overall cancer risk is comparable to that of the background population, and the increased risk of hepatobiliary cancer is likely an effect of coexisting liver disease and not causally related to IPAA.</p

Genetic Risk Scores Identify Genetic Aetiology of Inflammatory Bowel Disease Phenotypes

Background and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes. Methods: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p &lt;0.05) associations identified in cohort A were put forward for replication in cohort B. Results: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04]. Conclusions: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.</p

Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data

As custom arrays are cheaper than generic GWAS arrays, larger sample size is achievable for gene discovery. Custom arrays can tag more variants through denser genotyping of SNPs at associated loci, but at the cost of losing genome-wide coverage. Balancing this trade-off is important for maximizing experimental designs. We quantified both the gain in captured SNP-heritability at known candidate regions and the loss due to imperfect genome-wide coverage for inflammatory bowel disease using immunochip (iChip) and imputed GWAS data on 61 251 and 38 550 samples, respectively. For Crohn's disease (CD), the iChip and GWAS data explained 19 and 26% of variation in liability, respectively, and SNPs in the densely genotyped iChip regions explained 13% of the SNP-heritability for both the iChip and GWAS data. For ulcerative colitis (UC), the iChip and GWAS data explained 15 and 19% of variation in liability, respectively, and the dense iChip regions explained 10 and 9% of the SNP-heritability in the iChip and the GWAS data. From bivariate analyses, estimates of the genetic correlation in risk between CD and UC were 0.75 (SE 0.017) and 0.62 (SE 0.042) for the iChip and GWAS data, respectively. We also quantified the SNP-heritability of genomic regions that did or did not contain the previous 163 GWAS hits for CD and UC, and SNP-heritability of the overlapping loci between the densely genotyped iChip regions and the 163 GWAS hits. For both diseases, over different genomic partitioning, the densely genotyped regions on the iChip tagged at least as much variation in liability as in the corresponding regions in the GWAS data, however a certain amount of tagged SNP-heritability in the GWAS data was lost using the iChip due to the low coverage at unselected regions. These results imply that custom arrays with a GWAS backbone will facilitate more gene discovery, both at associated and novel loci

Prevalence of- and risk factors for work disability in Dutch patients with inflammatory bowel disease

AIM: To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess risk factors associated with work disability. METHODS: For this retrospective cohort study, we retrieved clinical data from the Dutch IBD Biobank on July 2014, containing electronic patient records of 3388 IBD patients treated in the eight University Medical Centers in the Netherlands. Prevalence of work disability was assessed in 2794 IBD patients and compared with the general Dutch population. Multivariate analyses were performed for work disability (sick leave, partial and full disability) and long-term full work disability (> 80% work disability for > 2 years). RESULTS: Prevalence of work disability was higher in Crohn's disease (CD) (29%) and ulcerative colitis (UC) (19%) patients compared to the general Dutch population (7%). In all IBD patients, female sex, a lower education level, and extra-intestinal manifestations, were associated with work disability. In CD patients, an age > 40 years at diagnosis, disease duration > 15 years, smoking, surgical interventions, and anti-TNFα use were associated with work disability. In UC patients, an age > 55 years, and immunomodulator use were associated with work disability. In CD patients, a lower education level (OR = 1.62, 95%CI: 1.02-2.58), and in UC patients, disease complications (OR = 3.39, 95%CI: 1.09-10.58) were associated with long-term full work disability. CONCLUSION: The prevalence of work disability in IBD patients is higher than in the general Dutch population. Early assessment of risk factors for work disability is necessary, as work disability is substantial among IBD patients

Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients

Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD). 1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown. 2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course