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

The Meta VCI Map consortium for meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping: design and multicenter pilot study

Introduction: The Meta VCI Map consortium performs meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping. Integration of data from different cohorts will increase sample sizes, to improve brain lesion coverage and support comprehensive lesion-symptom mapping studies. Methods: Cohorts with available imaging on white matter hyperintensities or infarcts and cognitive testing were invited. We performed a pilot study to test the feasibility of multicenter data processing and analysis and determine the benefits to lesion coverage. Results: Forty-seven groups have joined Meta VCI Map (stroke n = 7800 patients; memory clinic n = 4900; population-based n = 14,400). The pilot study (six ischemic stroke cohorts, n = 878) demonstrated feasibility of multicenter data integration (computed tomography/magnetic resonance imaging) and achieved marked improvement of lesion coverage. Discussion: Meta VCI Map will provide new insights into the relevance of vascular lesion location for cognitive dysfunction. After the successful pilot study, further projects are being prepared. Other investigators are welcome to join

Distribution of Cardioembolic Stroke : A Cohort Study

BACKGROUND: A cardiac origin in ischemic stroke is more frequent than previously assumed, but it is not clear which patients benefit from cardiac work-up if obvious cardiac pathology is absent. We hypothesized that thromboembolic stroke with a cardiac source occurs more frequently in the posterior circulation compared with thromboembolic stroke of another etiology. METHODS: We performed a multicenter observational study in 3,311 consecutive patients with ischemic stroke who were enrolled in an ongoing prospective stroke registry of 8 University hospitals between September 2009 and November 2014 in The Netherlands. In this initiative, the so-called Parelsnoer Institute-Cerebrovascular Accident Study Group, clinical data, imaging, and biomaterials of patients with stroke are prospectively and uniformly collected. We compared the proportions of posterior stroke location in patients with a cardiac stroke source with those with another stroke etiology and calculated risk ratios (RR) with corresponding 95% CI with Poisson regression analyses. To assess which patient or disease characteristics were most strongly associated with a cardiac etiology in patients with ischemic stroke, we performed a stepwise backward regression analysis. RESULTS: For the primary aim, 1,428 patients were eligible for analyses. The proportion of patients with a posterior stroke location among patients with a cardiac origin of their stroke (28%) did not differ statistically significant to those with another origin (25%), age and sex adjusted RR 1.16; 95% CI 0.96-1.41. For the secondary aim, 1,955 patients were eligible for analyses. No recent history of smoking, no hyperlipidemia, coronary artery disease, a higher age, and a higher National Institutes of Health Stroke Scale (NIHSS) score were associated with a cardiac etiology of ischemic stroke. CONCLUSIONS: We could not confirm our hypothesis that thromboembolic stroke localized in the posterior circulation is associated with a cardioembolic source of ischemic stroke, and therefore posterior stroke localization on itself does not necessitate additional cardiac examination. The lack of determinants of atherosclerosis, for example, no recent history of smoking and no hyperlipidemia, coronary artery disease, a higher age, and a higher NIHSS score are stronger risk factors for a cardiac source of ischemic stroke

Off-label prescriptions of drugs used for the treatment of Crohn’s disease or ulcerative colitis

Background: Off-label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off-label drugs for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before. Aim: To assess the proportion and characteristics of off-label prescribing for IBD in tertiary care centres in the Netherlands. Methods: A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off-label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni- and multivariable analyses were used to identify patient-specific characteristics predictive of increased off-label use. Results: For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off-label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off-label drugs. Commonly prescribed off-label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non-thiopurine/methotrexate off-label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off-label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off-label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001). Conclusion: About one-fifth of prescriptions for IBD were off-label and one-third of IBD patients, especially ulcerative colitis patients, were exposed to off-label drugs

Off-label prescriptions of drugs used for the treatment of Crohn’s disease or ulcerative colitis

Background: Off-label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off-label drugs for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before. Aim: To assess the proportion and characteristics of off-label prescribing for IBD in tertiary care centres in the Netherlands. Methods: A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off-label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni- and multivariable analyses were used to identify patient-specific characteristics predictive of increased off-label use. Results: For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off-label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off-label drugs. Commonly prescribed off-label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non-thiopurine/methotrexate off-label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off-label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off-label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001). Conclusion: About one-fifth of prescriptions for IBD were off-label and one-third of IBD patients, especially ulcerative colitis patients, were exposed to off-label drugs

A replication study of genetic risk loci for ischemic stroke in a Dutch population : A case-control study

We aimed to replicate reported associations of 10 SNPs at eight distinct loci with overall ischemic stroke (IS) and its subtypes in an independent cohort of Dutch IS patients. We included 1,375 IS patients enrolled in a prospective multicenter hospital-based cohort in the Netherlands, and 1,533 population-level controls of Dutch descent. We tested these SNPs for association with overall IS and its subtypes (large artery atherosclerosis, small vessel disease and cardioembolic stroke (CE), as classified by TOAST) using an additive multivariable logistic regression model, adjusting for age and sex. We obtained odds ratios (OR) with 95% confidence intervals (95% CI) for the risk allele of each SNP analyzed and exact p-values by permutation. We confirmed the association at 4q25 (PITX2) (OR 1.43; 95% CI, 1.13-1.81, p = 0.029) and 16q22 (ZFHX3) (OR 1.62; 95% CI, 1.26-2.07, p = 0.001) as risk loci for CE. Locus 16q22 was also associated with overall IS (OR 1.24; 95% CI, 1.08-1.42, p = 0.016). Other loci previously associated with IS and/or its subtypes were not confirmed. In conclusion, we validated two loci (4q25, 16q22) associated with CE. In addition, our study may suggest that the association of locus 16q22 may not be limited to CE, but also includes overall IS

Author Correction : A replication study of genetic risk loci for ischemic stroke in a Dutch population: a case-control study

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper

A replication study of genetic risk loci for ischemic stroke in a Dutch population: a case-control study

Abstract We aimed to replicate reported associations of 10 SNPs at eight distinct loci with overall ischemic stroke (IS) and its subtypes in an independent cohort of Dutch IS patients. We included 1,375 IS patients enrolled in a prospective multicenter hospital-based cohort in the Netherlands, and 1,533 population-level controls of Dutch descent. We tested these SNPs for association with overall IS and its subtypes (large artery atherosclerosis, small vessel disease and cardioembolic stroke (CE), as classified by TOAST) using an additive multivariable logistic regression model, adjusting for age and sex. We obtained odds ratios (OR) with 95% confidence intervals (95% CI) for the risk allele of each SNP analyzed and exact p-values by permutation. We confirmed the association at 4q25 (PITX2) (OR 1.43; 95% CI, 1.13–1.81, p = 0.029) and 16q22 (ZFHX3) (OR 1.62; 95% CI, 1.26–2.07, p = 0.001) as risk loci for CE. Locus 16q22 was also associated with overall IS (OR 1.24; 95% CI, 1.08–1.42, p = 0.016). Other loci previously associated with IS and/or its subtypes were not confirmed. In conclusion, we validated two loci (4q25, 16q22) associated with CE. In addition, our study may suggest that the association of locus 16q22 may not be limited to CE, but also includes overall IS

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

Frozen-Ground Cartoons: An international collaboration between artists and permafrost scientists

This project started in October 2015 with a crazy idea: prepare and submit a funding application for an international, multidisciplinary and non-traditional scientific outreach project… within the next 48 hours. Well, it worked out. A group of highly motivated young researchers from Canada and Europe united to combine arts and science and produce a series of outreach comic strips about permafrost (frozen ground). The aim of the project is to present and explain scientific research conducted across the circumpolar Arctic, placing emphasis on field work and the rapidly changing northern environment. The target audience is kids, youth, parents and teachers, with the general goal of making permafrost science more fun and accessible to the public. Because guess what : permafrost represents an area of more than twenty million km2 in the Northern Hemisphere, a huge area. As the climate warms, permafrost thaws and becomes unstable for houses, roads and airports. This rapid thawing of previously frozen ground also disrupts plant and animal habitats, impacts water quality and the ecology of lakes, and releases carbon into the atmosphere as greenhouse gases, making climate change even stronger. Hence permafrost and its response to climate change concerns us all. The project received initial support from the International Permafrost Association (IPA) as a targeted ‘Action Group’, and since then several other sponsors have joined the project. Here we are, now, two years after this first idea. What you are about to read is the result of an iterative process of exchanging ideas between artists and scientists. We first made an application call and received 49 applications from artists in 16 countries. Through a formal review process, we then selected two artists to work on this project: Noémie Ross from Canada, and Heta Nääs from Finland. With input from scientists, Noémie and Heta created fantastic cartoons that explain some of the changes happening to the environment in permafrost areas, how they affect people and wildlife, and what scientists are doing to better understand these changes to help people find innovative ways to adapt. We wish everyone plenty of fun reading this booklet and we would like to thank all those who supported this project