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Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways.

https://arctichealth.org/en/permalink/ahliterature153746
Source
PLoS Med. 2008 Dec 9;5(12):e239
Publication Type
Article
Date
Dec-9-2008
Author
Charlie W Lees
William J Zacharias
Mark Tremelling
Colin L Noble
Elaine R Nimmo
Albert Tenesa
Jennine Cornelius
Leif Torkvist
John Kao
Susan Farrington
Hazel E Drummond
Gwo-Tzer Ho
Ian D R Arnott
Henry D Appelman
Lauri Diehl
Harry Campbell
Malcolm G Dunlop
Miles Parkes
Sarah E M Howie
Deborah L Gumucio
Jack Satsangi
Author Affiliation
Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom.
Source
PLoS Med. 2008 Dec 9;5(12):e239
Date
Dec-9-2008
Language
English
Publication Type
Article
Keywords
Adult
Animals
England
Female
Gene Expression Profiling
Genetic Predisposition to Disease
Genetic Testing
Germ-Line Mutation
Hedgehog Proteins - genetics - physiology
Humans
Inflammation - genetics
Inflammatory Bowel Diseases - genetics
Male
Mice
Mice, Inbred C57BL
Middle Aged
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Scotland
Signal Transduction - genetics - immunology
Sweden
Transcription Factors - genetics
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.
Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.
HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.
Notes
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PubMed ID
19071955 View in PubMed
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Contribution of CARD15 variants in determining susceptibility to Crohn's disease in Sweden.

https://arctichealth.org/en/permalink/ahliterature169195
Source
Scand J Gastroenterol. 2006 Jun;41(6):700-5
Publication Type
Article
Date
Jun-2006
Author
Leif Törkvist
Colin L Noble
Mikael Lördal
Urban Sjöqvist
Ulrik Lindforss
Elaine R Nimmo
Richard K Russell
Robert Löfberg
Jack Satsangi
Author Affiliation
Department of Medical and Surgical Gastroenterology, Karolinska University Hospital, Stockholm, Sweden. leif.torkvist@ki.se
Source
Scand J Gastroenterol. 2006 Jun;41(6):700-5
Date
Jun-2006
Language
English
Publication Type
Article
Keywords
Alleles
Case-Control Studies
Crohn Disease - epidemiology - genetics
European Continental Ancestry Group
Female
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Humans
Intracellular Signaling Peptides and Proteins - genetics
Male
Multivariate Analysis
Mutation
Nod2 Signaling Adaptor Protein
Sweden - epidemiology
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. Mutations in the CARD15 gene have been associated with CD. No previous case-control CARD15 study has been performed in the Swedish population.
The study comprised of 321 individuals: 178 with CD and 143 healthy controls (HCs), all from Stockholm County. All were genotyped for the three main CD-associated CARD15 variants (R702W, G908R and 1007fs) and phenotypic associations were investigated.
The allele frequencies of the R702W variant (4.5% CD versus 0.7% HC, p=0.008, OR = 6.8) and the G908R variant (2.0% CD versus 0% HC, p=0.045) were more common in CD patients than in controls. No significant difference in1007fs variant allele frequency was found between CD patients and controls (2.0% CD versus 1.7% HC, p = 0.8, OR = 1.1). Carriage of CARD15 variants was more common in the CD patients than in controls (15.2% CD versus 4.2% HC, p = 0.001, OR = 4.1, population attributable risk (PAR) = 11.4%). Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18). An association between CARD15 variants and ileal CD (p=0.004, OR = 6.6) was confirmed by multivariate analyses.
The CARD15 variants R702W and G908R, but not 1007fs, are associated with susceptibility to CD in Stockholm County. Genotype-phenotype analysis shows an association with ileal CD. The contribution of these CARD15 mutations in Swedish CD patients overall is low in relation to studies elsewhere in Central Europe and North America, but is consistent with emerging data from elsewhere in Scandinavia and in Northern Europe.
PubMed ID
16716969 View in PubMed
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Contribution of the IBD5 locus to Crohn's disease in the Swedish population.

https://arctichealth.org/en/permalink/ahliterature164814
Source
Scand J Gastroenterol. 2007 Feb;42(2):200-6
Publication Type
Article
Date
Feb-2007
Author
Leif Törkvist
Colin L Noble
Mikael Lördal
Urban Sjöqvist
Ulrik Lindforss
Elaine R Nimmo
Robert Löfberg
Richard K Russell
Jack Satsangi
Author Affiliation
Department of Medical & Surgical Gastroenterology, Karolinska University Hospital, Stockholm, Sweden.
Source
Scand J Gastroenterol. 2007 Feb;42(2):200-6
Date
Feb-2007
Language
English
Publication Type
Article
Keywords
Adult
Chromosomes, Human, Pair 5 - genetics
Crohn Disease - epidemiology - genetics
Female
Follow-Up Studies
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Haplotypes
Humans
Incidence
Linkage Disequilibrium
Male
Middle Aged
Organic Cation Transport Proteins - genetics
Risk factors
Sweden - epidemiology
Abstract
Recent data have controversially suggested that variants of the organic cation transport genes SLC22A4 (OCTN1) and SLC22A5 (OCTN2) are responsible for the contribution of IBD5 to disease susceptibility in Crohn's disease (CD). The objective of this study was to assess the contribution of the SLC22A4 variant (1672T) and SLC22A5 variant (-207C) together with three IBD5 haplotype markers in the previously uninvestigated Swedish CD population.
The study comprised 178 CD patients and 143 healthy controls (HC). Genotyping for IBD5 single nucleotide polymorphisms (SNPs) IGR2096a_1, IGR2198a_1, IGR2230a_1, SLC22A4 1672T and SLC22A5 -207C was carried out using the TaqMan system. Associations with disease susceptibility and disease phenotype were investigated.
Strong linkage disequilibrium was observed between the investigated SNPs (D prime >0.92). IGR2096a_1 allelic frequency and homozygosity rates were associated with CD (44% CD versus 33.8% HC, p=0.008, OR=1.55 and 20% CD versus 12% HC, p=0.04, OR=1.93, respectively). Variant allelic frequency of SLC22A4, 1672T (44% versus 36%, p=0.03, OR=1.4) and homozygosity for the SLC22A4, SLC22A5 TC haplotype (1672T, -207C) (21.3% versus 12%, p=0.03, OR=1.78, population attributable risk (PAR)=11%) were associated with CD. There was no association between the allelic frequency of SLC22A5 and CD (46.6% CD versus 41.5% HC, p=0.82). The association of the TC haplotype with CD was not independent of the SNPs representing the extended IBD5 linkage interval.
The IBD5 locus is associated with CD in the Swedish population. The strongest association is with the marker SNP IGR2096a_1, lying p-telomeric to SLC22A4 and SLC22A5. The effect of the TC haplotype was not an independent determinant in this population.
PubMed ID
17340776 View in PubMed
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Cyclooxygenase-2 (COX-2) polymorphisms and risk of inflammatory bowel disease in a Scottish and Danish case-control study.

https://arctichealth.org/en/permalink/ahliterature141181
Source
Inflamm Bowel Dis. 2011 Apr;17(4):937-46
Publication Type
Article
Date
Apr-2011
Author
Vibeke Andersen
Elaine Nimmo
Henrik B Krarup
Hazel Drummond
Jane Christensen
Gwo-Tzer Ho
Mette Ostergaard
Anja Ernst
Charlie Lees
Bent A Jacobsen
Jack Satsangi
Ulla Vogel
Author Affiliation
Medical Department, Viborg Regional Hospital, Viborg, Denmark. va9791@gmail.com
Source
Inflamm Bowel Dis. 2011 Apr;17(4):937-46
Date
Apr-2011
Language
English
Publication Type
Article
Keywords
Adult
Aged
Biological Markers - metabolism
Case-Control Studies
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Cyclooxygenase 2 - genetics
DNA - genetics
Denmark
Female
Gene Frequency
Genotype
Humans
Male
Middle Aged
Polymerase Chain Reaction
Polymorphism, Genetic - genetics
Scotland
Young Adult
Abstract
Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors.
Genotypes of the COX-2/PTGS2/PGHS2 A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) polymorphisms were assessed in a Scottish and Danish case-control study including 732 Crohn's disease (CD) cases, 973 ulcerative colitis (UC) cases, and 1157 healthy controls using logistic regression.
Carriers of the COX-2 A-1195G variant allele had increased risk of UC (odds ratio [OR], 95% confidence interval [CI] = 1.25 [1.02-1.54], P = 0.03) and of both UC and IBD among never smokers (OR [95% CI] = 1.47 [1.11-1.96], P = 0.01 and OR [95% CI] = 1.37 [1.06-1.77], P = 0.02, respectively). Furthermore, this variant genotype was associated with increased risk of diagnosis of UC before age 40 years and with extensive UC (OR [95% CI] = 1.34 [1.11-1.62], P = 0.002 and OR [95% CI] = 1.32 [1.03-1.69], P = 0.03, respectively).
COX-2 A-1195G polymorphism was associated with the risk of UC, especially among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD.
PubMed ID
20803508 View in PubMed
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Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity.

https://arctichealth.org/en/permalink/ahliterature281741
Source
World J Gastroenterol. 2016 Jun 07;22(21):5050-9
Publication Type
Article
Date
Jun-07-2016
Author
Frederik Trier Moller
Lina Knudsen
Marcus Harbord
Jack Satsangi
Hannah Gordon
Lene Christiansen
Kaare Christensen
Tine Jess
Vibeke Andersen
Source
World J Gastroenterol. 2016 Jun 07;22(21):5050-9
Date
Jun-07-2016
Language
English
Publication Type
Article
Keywords
Adult
Aged
Anti-Inflammatory Agents - therapeutic use
Biomarkers - analysis
Biopsy
Case-Control Studies
Cohort Studies
Colectomy
Colitis, Ulcerative - diagnosis - genetics - metabolism - therapy
Crohn Disease - diagnosis - genetics - metabolism - therapy
Denmark
Diseases in Twins - diagnosis - genetics - metabolism - therapy
Endoscopy, Gastrointestinal
Female
Gastrointestinal Agents - therapeutic use
Humans
Immunosuppressive Agents - therapeutic use
Leukocyte L1 Antigen Complex - analysis
Male
Middle Aged
Phenotype
Registries
Severity of Illness Index
Twins, Monozygotic - genetics
Up-Regulation
Abstract
To describe the establishment of a Danish inflammatory bowel diseases (IBD) twin cohort with focus on concordance of treatment and inflammatory markers.
We identified MZ twins, likely to be discordant or concordant for IBD, by merging information from the Danish Twin Register and the National Patient Register. The twins were asked to provide biological samples, questionnaires, and data access to patient files and public registries. Biological samples were collected via a mobile laboratory, which allowed for immediate centrifugation, fractionation, and storage of samples. The mean time from collection of samples to storage in the -80 °C mobile freezer was less than one hour. The diagnoses where validated using the Copenhagen diagnostic criteria.
We identified 159 MZ IBD twin pairs, in a total of 62 (39%) pairs both twins agreed to participate. Of the supposed 62 IBD pairs, the IBD diagnosis could be confirmed in 54 pairs. The cohort included 10 concordant pairs, whereof some were discordant for either treatment or surgery. The 10 concordant pairs, where both pairs suffered from IBD, included eight CD/CD pairs, one UC/UC pair and one UC/IBDU pair. The discordant pairs comprised 31 UC, 5 IBDU (IBD unclassified), and 8 CD discordant pairs. In the co-twins not affected by IBD, calprotectin was above 100 µg/g in 2 participants, and above 50 µg/g in a further 5 participants.
The presented IBD twin cohorts are an excellent resource for bioinformatics studies with proper adjustment for disease-associated exposures including medication and inflammatory activity in the co-twins.
Notes
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PubMed ID
27275097 View in PubMed
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PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.

https://arctichealth.org/en/permalink/ahliterature150812
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Publication Type
Article
Date
Oct-2009
Author
Marco Zucchelli
Leif Torkvist
Francesca Bresso
Jonas Halfvarson
Anna Hellquist
Francesca Anedda
Ghazaleh Assadi
Gunnar B Lindgren
Monika Svanfeldt
Martin Janson
Colin L Noble
Sven Pettersson
Maarit Lappalainen
Paulina Paavola-Sakki
Leena Halme
Martti Färkkilä
Ulla Turunen
Jack Satsangi
Kimmo Kontula
Robert Löfberg
Juha Kere
Mauro D'Amato
Author Affiliation
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Date
Oct-2009
Language
English
Publication Type
Article
Keywords
Adult
Case-Control Studies
Cohort Studies
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Female
Finland
Genotype
Humans
Male
Middle Aged
NF-kappa B - genetics - metabolism
Nod2 Signaling Adaptor Protein - genetics - metabolism
Polymorphism, Single Nucleotide - genetics
Sweden
Symporters - genetics
Abstract
Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD.
Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB.
The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P
PubMed ID
19462432 View in PubMed
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Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease.

https://arctichealth.org/en/permalink/ahliterature165784
Source
Inflamm Bowel Dis. 2007 May;13(5):531-6
Publication Type
Article
Date
May-2007
Author
Francesca Bresso
Johan Askling
Marco Astegiano
Brunello Demarchi
Nicoletta Sapone
Mario Rizzetto
Paolo Gionchetti
Karen M Lammers
Annalisa de Leone
Gabriele Riegler
Elaine R Nimmo
Hazel Drummond
Colin Noble
Leif Torkvist
Anders Ekbom
Marco Zucchelli
Robert Lofberg
Jack Satsangi
Sven Pettersson
Mauro D'Amato
Author Affiliation
Strategic Research Center IRIS, Karolinska Institutet, Stockholm, Sweden.
Source
Inflamm Bowel Dis. 2007 May;13(5):531-6
Date
May-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Crohn Disease - genetics - pathology - physiopathology
Cystic Fibrosis Transmembrane Conductance Regulator - genetics - physiology
Female
Genetic Predisposition to Disease
Genotype
Heterozygote Detection
Humans
Italy
Male
Middle Aged
Mutation
Phenotype
Scotland
Sweden
Abstract
Inflammatory bowel disease (IBD) is an epithelial barrier disease that is thought to result from a dysregulated interaction with bacteria in the intestine of genetically predisposed individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in the autosomal recessive disease cystic fibrosis, modulates gut permeability, mucus production, and epithelial interactions with bacteria. The cystic fibrosis DeltaF508 mutation is commonly found in the general population and has been shown to result in a reduced number of CFTR molecules at the surface of epithelial cells. Given the important biological functions of CFTR in the intestine, we tested whether this mutation is of relevance to IBD.
Using DNA heteroduplex analysis, we investigated the distribution of DeltaF508 heterozygosity in 2568 subjects from three independent cohorts of Italian, Swedish, and Scottish IBD patients and controls.
In all three cohorts an association between DeltaF508 and Crohn's disease (CD) was observed. Specifically, DeltaF508 heterozygosity was markedly underrepresented in CD patients from Italy and Sweden (P = 0.021 and 0.027 versus controls, respectively), while stratification for disease location revealed an absence of DeltaF508 carriers among Scottish CD patients with right-sided colitis (P = 0.023 versus all other locations).
DeltaF508 heterozygosity might exert a protective effect in CD.
PubMed ID
17206681 View in PubMed
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7 records – page 1 of 1.