Rinse K Weersma

University of Groningen, Groningen, Groningen, Netherlands

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Publications (150)1412.05 Total impact

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    ABSTRACT: Background: Cigarette smoking ameliorates ulcerative colitis (UC) and aggravates Crohn's disease (CD). Cigarette smoke suppresses inflammation-induced apoptosis in intestinal epithelial cells (DLD-1), which may explain its protective effect in UC. Here, we performed transcriptome profiling of cigarette smoke extract (CSE)-exposed DLD-1 and Jurkat cells (T-lymphocytes) and related this to UC susceptibility genes with protective functions in the intestinal epithelium. Methods: CSE-regulated genes in DLD-1 and Jurkat cells were identified by Illumina microarrays and compared to genes in UC susceptibility loci. Colon biopsies were analyzed by immunohistochemistry for cell-specific expression of HSPA6. CSE-induced gene expression was analyzed by Q-PCR, Western blotting and immunofluorescence microscopy. Protein (HSPA6/Bcl-XL) interactions were analyzed by immunoprecipitation. Results: CSE changed the expression of 536 and 2560 genes in DLD-1 and Jurkat cells, respectively. The "response to unfolded protein" was one of the most significantly affected gene sets with prominent induction (20.3-fold) of heat shock protein A6 (HSPA6). Six CSE-induced genes in DLD-1 cells were located in UC-susceptibility loci, including HSPA6 (rs1801274). HSPA6 is highly expressed in the human colonic epithelium. CSE caused a dose-dependent strong (>100-fold at 30% CSE for 6h), but transient induction of HSPA6 mRNA and protein in DLD-1 cells. HSPA6 co-immune precipitated with anti-apoptotic Bcl-XL, protein levels of which were increased while mRNA levels were unchanged. Conclusions: HSPA6 is a cigarette smoke-induced UC-susceptibility gene. The HSPA6 risk locus is associated with decreased HSPA6 expression. HSPA6 provides epithelial protection by stabilizing anti-apoptotic Bcl-XL, thereby contributing to the beneficial effect of cigarette smoking in UC.
    No preview · Article · Jan 2016 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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    ABSTRACT: Celiac disease (CeD) is a gluten triggered, immune-mediated disease of the small intestine. Few clinical cohort descriptions are available, despite the diverse clinical picture. This study provides an overview of a large Dutch CeD cohort focusing on presenting symptoms, co-occurrence of immune mediated diseases (IMD) and malignancies.
    No preview · Article · Jan 2016
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    ABSTRACT: Background and aims: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. Methods: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. Results: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. Conclusions: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.
    Full-text · Article · Dec 2015 · Gut
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    ABSTRACT: Background & AimsNephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so these drugs can be avoided, or monitoring intensified, in high-risk patients.Methods Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome wide association study was then undertaken with these cases and 4,109 disease controls.ResultsAfter adjudication, 151 cases of 5-ASA induced nephrotoxicity were identified. 68% of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% CI 2.3 - 3.7). Only 30% of cases recovered completely after drug withdrawal with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (P=1x10(-7)) with 5-ASA induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n=55) significantly strengthened this association (P=4x10(-9), Odds Ratio 3.1).Conclusions This is the largest and most detailed study of 5-ASA induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to a drug induced renal injury.
    No preview · Article · Nov 2015 · Journal of Crohn s and Colitis
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    ABSTRACT: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
    Full-text · Article · Oct 2015 · The Lancet
  • A Boudewijn de Vries · R K Weersma
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    ABSTRACT: Primary sclerosing cholangitis is a rare chronic liver disease of unknown etiology for which the only known curative treatment is liver transplantation. The disease is defined by progressive inflammation and fibrosis of the bile ducts, causing biliary strictures and cholestasis. Common complications of the disease are presence of biliary lithiasis requiring stone extraction and development of dominant bile duct strictures requiring balloon dilatation and stent placement through endoscopic retrograde cholangiopancreatography. The increased development of cholangiocarcinoma is a dreaded complication in PSC, as it is often detected in an advanced stage and is associated with a poor prognosis. Several endoscopic techniques, including endoscopic ultrasound, confocal laser endomicroscopy and peroral cholangioscopy are applied in the management of PSC and detection of cholangiocarcinoma. Tissue sampling through different types of biopsies and biliary brush combined with fluorescence in situ hybridization are used to differentiate benign dominant strictures from biliary neoplasia. Nonetheless early detection of cholangiocarcinoma in PSC remains a clinical challenge requiring a specialized diagnostic workup. The aim of this review is to discuss the role of diagnostic and therapeutic endoscopy in management of PSC, providing an overview of current literature.
    No preview · Article · Oct 2015
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    ABSTRACT: Rationale: Evidence suggests the gut microbiome is involved in the development of cardiovascular disease (CVD), with the host-microbe interaction regulating immune and metabolic pathways. However, there was no firm evidence for associations between microbiota and metabolic risk factors for CVD from large-scale studies in humans. In particular, there was no strong evidence for association between CVD and aberrant blood lipid levels Objective: To identify intestinal bacteria taxa, whose proportions correlate with body mass index (BMI) and lipid levels, and to determine whether lipid variance can be explained by microbiota relative to age, gender and host genetics. Methods and results: We studied 893 subjects from the LifeLines-DEEP population cohort. After correcting for age and gender, we identified 34 bacterial taxa associated to BMI and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota explain 4.5% of the variance in BMI, 6% in triglycerides, and 4% in high-density lipoproteins (HDL), independent of age, gender and genetic risk factors. A novel risk model including the gut microbiome explained up to 25.9% of HDL variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on low-density lipoproteins or total cholesterol. Conclusions: Our studies suggest that the gut microbiome may play an important role in the variation in BMI and blood lipid levels, independent of age, gender and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body mass, triglycerides and HDL.
    Full-text · Article · Sep 2015 · Circulation Research
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    ABSTRACT: Background: Hidradenitis suppurativa (HS) has recently been associated with inflammatory bowel disease (IBD). The objective of this study is to investigate the prevalence of HS in IBD and to identify clinical and genetic parameters associated with HS in IBD. Methods: A questionnaire, validated for HS, was sent to 1969 patients suffering from IBD. Results: The prevalence of HS in our IBD cohort (1260 participating patients) was significantly higher than in the general population (6.8%-10.6% versus 1%-2%). IBD patients with HS were affected by IBD significantly earlier and more often treated with anti-TNF-α therapy and surgical resection compared to IBD without HS. Female gender, smoking, a higher body mass index, and younger age were independent associated parameters for HS. Within cases allelic association analysis was performed for 59 cases (IBD with HS) and 293 controls (IBD without HS). We observed 2 promising new associations in genomic regions harboring ELOVL7 (rsnumber 10057395 P = 7.15 × 10, odds ratio = 0.4), and in the intergenic region between SULT1B1 and SULT1E1 (rsnumber 2014777 P = 7.48 × 10, odds ratio = 2.3). Conclusions: HS is present in 6.8% to 10.6% of IBD patients. Co-morbid HS is associated with an early onset of IBD in which anti-tumor necrosis factor-α therapy and surgical resections are often needed. We identified a suggestive protective association with ELOVL7 and suggestive risk association with the genes SULT1B1 and SULT1E1 for HS, in the context of IBD. These genetic associations need further exploration and replication in additional independent cohorts.
    No preview · Article · Sep 2015 · Inflammatory Bowel Diseases
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    ABSTRACT: Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.
    Full-text · Article · Jul 2015 · Nature Genetics
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    ABSTRACT: Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.95.
    No preview · Article · May 2015 · European journal of human genetics: EJHG
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    ABSTRACT: Author Summary Many variants in the genome, including variants associated with disease, affect the expression of genes. These so-called expression quantitative trait loci (eQTL) can be used to gain insight in the downstream consequences of disease. While it has been shown that many disease-associated variants alter gene expression in a cell-type dependent manner, eQTL datasets for specific cell types may not always be available and their sample size is often limited. We present a method that is able to detect cell type specific effects within eQTL datasets that have been generated from whole tissues (which may be composed of many cell types), in our case whole blood. By combining numerous whole blood datasets through meta-analysis, we show that we are able to detect eQTL effects that are specific for neutrophils and lymphocytes (two blood cell types). Additionally, we show that the variants associated with some diseases may preferentially alter the gene expression in one of these cell types. We conclude that our method is an alternative method to detect cell type specific eQTL effects, that may complement generating cell type specific eQTL datasets and that may be applied on other cell types and tissues as well.
    Full-text · Article · May 2015 · PLoS Genetics
  • Siew C Ng · Charlie W. Lees · Rinse K. Weersma

    No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: To see if SNPs could help predict response to biological therapy using adalimumab (ADA) in Crohn's disease (CD). IBDQ index and CRP levels were used to monitor therapy response. We genotyped 31 CD-associated genes in 102 Slovenian CD patients. The strongest association for treatment response defined as decrease in CRP levels was found for ATG16L1 SNP rs10210302. Additional SNPs in 7 out of 31 tested CD-associated genes (PTGER4, CASP9, IL27, C11orf30, CCNY, IL13, NR1I2) showed suggestive association with ADA response. Our results suggest ADA response in CD patients is genetically predisposed by SNPs in CD risk genes and suggest ATG16L1 as most promising candidate gene for drug response in ADA treatment. Original submitted 24 September 2014; Revision submitted 1 December 2014.
    No preview · Article · Mar 2015 · Pharmacogenomics
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    ABSTRACT: To review the current literature for the specific clinical characteristics of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC). A systematical review for clinical characteristics of IBD in PSC was performed by conducting a broad search for "primary sclerosing cholangitis" in Pubmed. "Clinical characteristics" were specified into five predefined subthemes: epidemiology of IBD in PSC, characteristics of IBD in PSC (i.e., location, disease behavior), risk of colorectal cancer development, IBD recurrence and de novo disease after liver transplantation for PSC, and safety and complications after proctocolectomy with ileal pouch-anal anastomosis. Papers were selected for inclusion based on their relevance to the subthemes, and were reviewed by two independent reviewers. Only full papers relevant to PSC-IBD were included. Additionally the references of recent reviews for PSC (< 5 years old) were scrutinized for relevant articles. Initial literature search for PSC yielded 4704 results. After careful review 65 papers, comprising a total of 11406 PSC-IBD patients, were selected and divided according to subtheme. Four manuscripts overlapped and were included in two subthemes. Prevalence of IBD in PSC shows a large variance, ranging from 46.5% to 98.7% with ulcerative colitis (UC) being the most common type (> 75%). The highest IBD rates in PSC are found in papers reviewing both endoscopic and histological data for IBD diagnosis. Although IBD in PSC is found to be a quiescent disease, pancolitis occurs often, with rates varying from 35% to 95%. Both backwash ileitis and rectal sparing are observed infrequently. The development of dysplasia or colorectal carcinoma is increased in PSC-IBD; the cumulative 10 years risk varying between 0% and 11%. Exacerbation of IBD is common after liver transplantation for PSC and de novo disease is seen in 1.3% to 31.3% of PSC-IBD patients. The risk for development of pouchitis in PSC-IBD is found to be significant, affecting 13.8% to 90% of the patients after proctocolectomy with ileo anal-pouch anastomosis. IBD in primary sclerosing cholangitis represents a distinct phenotype that differs from UC and Crohn's disease and therefore requires specialized management.
    Preview · Article · Feb 2015
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    ABSTRACT: Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut. The etiology of IBD is complex, involving genetic as well as environmental factors. Genetic studies have identified 163 genetic risk loci for IBD, which have led to new insights into the biological mechanisms of the disease. The currently known IBD risk loci show an almost 75% overlap with genetic risk loci for other immune mediated diseases. Current studies are focused on the translation of the identified risk loci to clinical practice. The first steps towards this translation are being taken with the identification of genetic risk factors for drugs toxicity, specific disease course and response to therapy. In this review we will discuss how the IBD genetic risk loci were identified and how this knowledge can be translated towards clinical practice.
    No preview · Article · Dec 2014 · Expert Review of Clinical Immunology
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    ABSTRACT: Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease. We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways. We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways. These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.
    Full-text · Article · Dec 2014 · Genome Medicine
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    ABSTRACT: Objective Crohn's disease (CD) is caused by a complex interplay among genetic, microbial and environmental factors. ATG16L1 is an important genetic factor involved in innate immunity, including autophagy and phagocytosis of microbial components from the gut. We investigated the effect of inflammation on the composition of microbiota in the ileal mucosa of CD patients in relation to the ATG16L1 risk status. Design Biopsies (n=35) were obtained from inflamed and non-inflamed regions of the terminal ileum of 11 CD patients homozygous for the ATG16L1 risk allele (ATG16L1-T300A) and 9 CD patients homozygous for the ATG16L1 protective allele (ATG16L1-T300). Biopsy DNA was extracted and the bacterial composition analysed by pyrosequencing. Intracellular survival rates of adherent-invasive Escherichia coli (AIEC) were analysed by determining colony forming units after exposure to monocytes isolated from healthy volunteers homozygous for the ATG16L1 risk or protective allele. Results Inflamed ileal tissue from patients homozygous for the ATG16L1 risk allele contained increased numbers of Fusobacteriaceae, whereas inflamed ileal tissue of patients homozygous for the ATG16L1 protective allele showed decreased numbers of Bacteroidaceae and Enterobacteriaceae and increased Lachnospiraceae. The ATG16L1 allele did not affect the bacterial composition in the non-inflamed ileal tissue. Monocytes homozygous for the ATG16L1 risk allele showed impaired killing of AIEC under inflammatory conditions compared with those homozygous for the ATG16L1 protective allele. Conclusions CD patients homozygous for the ATG16L1–T300A risk allele show impaired clearance of pathosymbionts in ileal inflammation indicating that ATG16L1 is essential for effective elimination of pathosymbionts upon inflammation.
    Full-text · Article · Sep 2014 · Gut
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    ABSTRACT: Background In up to 30 percent of small bowel capsule endoscopy procedures, the capsule does not reach the cecum within recording time. A prolonged gastric transit time has been recognized as a risk factor for incomplete capsule endoscopy. The aim of this study was to analyze if a single dose of orally administered erythromycin prior to capsule endoscopy results in a higher completion rate compared to orally administered domperidone. Methods Single centre, non-concurrent prospective cohort study, 649 capsule endoscopy procedures were included. Cecal completion rates, gastric and small bowel transit times and diagnostic yield were analyzed. Results 239 patients received erythromycin, 410 patients received domperidone. The cecal completion rate was 86% after erythromycin versus 80% after domperidone (p = 0.03). After excluding known risk factors for incomplete capsule endoscopy such as hospitalization and previous abdominal surgery, erythromycin still resulted in an increased completion rate (p = 0.04). Median gastric transit time was lower after erythromycin compared to domperidone (13 min versus 22 min, p < 0.001). Median small bowel transit times were similar in both groups (236 min versus 248 min, p = 0.21). Conclusions In this study, the largest to date on this subject, the cecal completion rate was higher with erythromycin than with domperidone, but there was no difference in the diagnostic yield.
    Preview · Article · Sep 2014 · BMC Gastroenterology
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    ABSTRACT: Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
    Full-text · Article · Sep 2014 · Nature Genetics
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    E.A.M. Festen · R.K. Weersma
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    ABSTRACT: Inflammatory bowel disease, consisting of Crohn’s disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its chronic and relapsing nature gives rise to a high disease burden both financially, physically and psychologically. Current therapy still cannot prevent the need for surgical intervention in more than half of IBD patients. Consequently, advances in IBD therapy are of high importance. Recently, several new forms of targeted therapy have been introduced, which should improve surgery-free prognosis of IBD patients. Recent identification of genetic risk variants for IBD has led to new insights into the biological mechanisms of the disease, which will, in the future, lead to new targeted therapy. In the meantime repositioning of drugs from biologically similar diseases towards IBD might lead to new IBD therapies.
    Preview · Article · Jun 2014 · Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology

Publication Stats

7k Citations
1,412.05 Total Impact Points

Institutions

  • 2004-2016
    • University of Groningen
      • Department of Gastroenterology and Hepatology
      Groningen, Groningen, Netherlands
  • 2005-2011
    • Universitair Medisch Centrum Groningen
      • Department of Gastroenterology and Hepatology
      Groningen, Groningen, Netherlands