[Show abstract][Hide abstract] 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.
The Lancet 10/2015; DOI:10.1016/S0140-6736(15)00465-1 · 45.22 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
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.
Circulation Research 09/2015; 117(9). DOI:10.1161/CIRCRESAHA.115.306807 · 11.02 Impact Factor
[Show abstract][Hide abstract] 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.
A questionnaire, validated for HS, was sent to 1969 patients suffering from IBD.
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).
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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
European journal of human genetics: EJHG 05/2015; DOI:10.1038/ejhg.2015.95 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Genome Medicine 12/2014; 6(12):107. DOI:10.1186/s13073-014-0107-1 · 5.34 Impact Factor
[Show abstract][Hide abstract] 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.
Gut 09/2014; 64(10). DOI:10.1136/gutjnl-2014-307289 · 14.66 Impact Factor
[Show abstract][Hide abstract] 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.
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.
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).
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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Baillière' s Best Practice and Research in Clinical Gastroenterology 06/2014; 28(3). DOI:10.1016/j.bpg.2014.04.002 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective Over 100 ulcerative colitis (UC) loci have been identified by genome-wide association studies (GWASs) primarily in Caucasians (CEUs). Many of them have weak effects on disease susceptibility, and the bulk of the heritability cannot be ascribed to these loci. Very little is known about the genetic background of UC in non-CEU groups. Here we report the first GWAS on UC in a genetically distinct north Indian (NI) population.
Design A genome-wide scan was performed on 700 cases and 761 controls. 18 single-nucleotide polymorphisms (SNPs) (p<5×10−5) were genotyped in an independent cohort of 733 cases and 1148 controls. A linear mixed model was used for case–control association tests.
Results Seven novel human leucocyte antigen (HLA)-independent SNPs from chromosome 6, located in 3.8-1, BAT2, MSH5, HSPA1L, SLC44A4, CFB and NOTCH4, exceeded p<5×10−8 in the combined analysis. To assess the independent biological contribution of such genes from the extended HLA region, we determined the percentage alternative pathway activity of complement factor B (CFB), the top novel hit. The activity was significantly different (p=0.01) between the different genotypes at rs12614 in UC cases. Transethnic comparisons revealed a shared contribution of a fraction of UC risk genes between NI and CEU populations, in addition to genetic heterogeneity.
Conclusions This study shows varying contribution of the HLA region to UC in different populations. Different environmental exposures and the characteristic genetic structure of the HLA locus across ethnic groups collectively make it amenable to the discovery of causative alleles by transethnic resequencing. This may lead to an improved understanding of the molecular mechanisms underlying UC.
Gut 05/2014; 64(4). DOI:10.1136/gutjnl-2013-306625 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.
Science translational medicine 04/2014; 6(233):233ra53. DOI:10.1126/scitranslmed.3006763 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical presentation of the inflammatory bowel diseases (IBD) is extremely heterogenous and is characterized by various extraintestinal manifestations and complications (EIM). Increasing genetic insight for IBD and EIM shows multiple shared susceptibility loci. We hypothesize that, next to these overlapping genetic risk loci, distinct disease pathways are shared between IBD and EIM.
The overlapping genetic risk loci for IBD and its EIM were searched in literature. We assessed shared disease pathways by performing an extensive pathway analysis by protein-protein interaction and cotranscriptional analysis, using both publicly available and newly developed databases.
Reliable genetic data were available for primary sclerosing cholangitis, ankylosing spondylitis, decreased bone mineral density, colorectal carcinoma, gallstones, kidney stones, and deep venous thrombosis. We found an extensive overlap in genetic risk loci, especially for IBD and primary sclerosing cholangitis and ankylosing spondylitis. We identified 370 protein-protein interactions, of which 108 are statistically specific. We identified 446 statistically specific cotranscribed gene pairs. The interactions are shown to cluster in specific biological pathways.
We show that the pathogenetic overlap between IBD and its EIM extends beyond shared risk genes to distinctive shared biological pathways. We define genetic background as a risk factor for IBD-EIM alongside known mechanisms such as malabsorption and medication. Clustering patients based on distinctive pathways may enable stratification of patients to predict development of EIM.