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Clough J, Colwill M, Poullis A, Pollok R, Patel K, Honap S. Biomarkers in inflammatory bowel disease: a practical guide. Therap Adv Gastroenterol 2024; 17:17562848241251600. [PMID: 38737913 PMCID: PMC11085009 DOI: 10.1177/17562848241251600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/12/2024] [Indexed: 05/14/2024] Open
Abstract
Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.
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Affiliation(s)
- Jennie Clough
- St George’s University Hospitals NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Michael Colwill
- St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Andrew Poullis
- St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Richard Pollok
- St George’s University Hospital NHS Foundation Trust
- Institute of Infection and Immunity, St George’s University, London, UK
| | - Kamal Patel
- St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Sailish Honap
- St George’s University Hospitals NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
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Steiner CA, Berinstein JA, Louissaint J, Higgins PDR, Spence JR, Shannon C, Lu C, Stidham RW, Fletcher JG, Bruining DH, Feagan BG, Jairath V, Baker ME, Bettenworth D, Rieder F. Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review. Clin Gastroenterol Hepatol 2022; 20:817-846.e10. [PMID: 34089850 PMCID: PMC8636551 DOI: 10.1016/j.cgh.2021.05.054] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. METHODS We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). RESULTS Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. CONCLUSIONS There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
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Affiliation(s)
- Calen A Steiner
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Jeffrey A Berinstein
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jeremy Louissaint
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Peter D R Higgins
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jason R Spence
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Carol Shannon
- Taubman Health Sciences Library, University of Michigan, Ann Arbor, Michigan
| | - Cathy Lu
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Ryan W Stidham
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | | | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Brian G Feagan
- Alimentiv Inc, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Biostatistics and Epidemiology, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Alimentiv Inc, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Biostatistics and Epidemiology, Western University, London, Ontario, Canada
| | - Mark E Baker
- Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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Siddique I, Mustafa AS, Khan I, Ziyab AH, Altarrah M, Sulaiman R, Kadungothayil N, Shaheed F. Detection of mutations in NOD2/CARD15 gene in Arab patients with Crohn's disease. Saudi J Gastroenterol 2021; 27:240-248. [PMID: 34380868 PMCID: PMC8448013 DOI: 10.4103/sjg.sjg_582_20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Mutations in NOD2/CARD15 gene have been linked to an increased risk of Crohn's disease (CD). The objective of this study is to determine NOD2/CARD15 gene mutations, and their association with the risk of CD in Arabs in Kuwait. METHODS Four NOD2 gene mutations, including Pro268Ser (SNP5), Arg702Trp (SNP8), Gly908Arg (SNP12), and Leu1007FsinsC (SNP13) were examined in Arab CD patients (n = 103) and control subjects (n = 100). The genomic DNA was isolated and used in polymerase chain reaction (PCR) with four sets of specific primers. The PCR-amplified DNA fragments were sequenced and analyzed for the NOD2 mutations. Logistic regression was used to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS Of the four genotyped variants, the Arg702Trp (SNP8) and Leu1007FsinsC (SNP13) variants were not informative in our study sample due to minor allele frequency of <1%. The Pro268Ser (SNP5) mutation was detected in 17 (16.5%) CD patients and 32 (32.0%) controls. The Gly908Arg (SNP12) mutation was observed in 24 (23.3%) patients and 10 (10.0%) controls. In the dominant genetic risk model (i.e. carrying at least one minor allele), CD patients compared to controls were less likely to carry either the "CT" or "TT" genotype of variant Pro268Ser (SNP5; aOR = 0.43, 95% CI: 0.22-0.84). In contrast, CD patients compared to controls were more likely to carry the homozygous for the minor allele or the heterozygous genotypes of variant Gly908Arg (SNP12; aOR = 2.67, 95% CI: 1.19-5.97). CONCLUSIONS In this Arab population, carrying at least one copy of the minor allele of Gly908Arg (SNP12) mutation in NOD2 gene was associated with increased susceptibility to CD, while having the heterozygous or homozygous for the minor allele genotype of the Pro268Ser (SNP5) mutation provided protection against CD. Mutations in Arg702Trp (SNP8) and Leu1007FsinsC (SNP13) were not detected in this sample of the Arab population in Kuwait.
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Affiliation(s)
- Iqbal Siddique
- Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Al-Amiri Hospital, Kuwait,Thunayan Al-Ghanim Gastroenterology Center, Al-Amiri Hospital, Kuwait,Address for correspondence: Prof. Iqbal Siddique, Department of Medicine, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat - 13110, Kuwait. E-mail:
| | - Abu S. Mustafa
- Department of Microbiology, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait,Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Islam Khan
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Ali H. Ziyab
- Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Munira Altarrah
- Thunayan Al-Ghanim Gastroenterology Center, Al-Amiri Hospital, Kuwait
| | - Riyas Sulaiman
- Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Numeer Kadungothayil
- Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Faraz Shaheed
- Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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Brudek T. Inflammatory Bowel Diseases and Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2019; 9:S331-S344. [PMID: 31609699 PMCID: PMC6839501 DOI: 10.3233/jpd-191729] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 09/20/2019] [Indexed: 12/19/2022]
Abstract
The etiology of Parkinson's disease (PD) is multifactorial, with genetics, aging, and environmental agents all a part of the PD pathogenesis. Widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites, and degeneration of substantia nigra dopamine neurons are the pathological hallmarks of PD. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. Experimental, clinical and epidemiological data suggest that intestinal inflammation contributes to the pathogenesis of PD, and the increasing number of studies suggests that the condition may start in the gastrointestinal system years before any motor symptoms develop. Patients with inflammatory bowel disease (IBD) have a higher risk of developing PD compared with non-IBD individuals. Gene association study has found a genetic link between IBD and PD, and an evidence from animal studies suggests that gut inflammation, similar to that observed in IBD, may induce loss of dopaminergic neurons. Based on preclinical models of PD, it is suggested that the enteric microbiome changes early in PD, and gut infections trigger α-synuclein release and aggregation. In this paper, the possible link between IBD and PD is reviewed based on the available literature. Given the potentially critical role of gastrointestinal pathology in PD pathogenesis, there is reason to suspect that IBD or its treatments may impact PD risk. Thus, clinicians should be aware of PD symptoms in IBD patients.
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Affiliation(s)
- Tomasz Brudek
- Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
- Copenhagen Center for Translational Research, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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Icduygu FM, Erdogan MO, Ulasli SS, Yildiz HG, Celik ZS, Unlu M, Solak M. Is There an Association Between NOD2 Gene Polymorphisms and Chronic Obstructive Pulmonary Disease Progression? INT J HUM GENET 2017. [DOI: 10.1080/09723757.2017.1351118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Fadime Mutlu Icduygu
- Department of Medical Genetics, Faculty of Medicine, Giresun University, Giresun, 28100, Turkey
| | - Mujgan Ozdemir Erdogan
- Department of Medical Genetics, Faculty of Medicine, Afyon Kocatepe University, Afyon, 03200, Turkey
| | - Sevinc Sarinc Ulasli
- Department of Pulmonary Diseases, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey
| | - Handan Gonenli Yildiz
- Department of Medical Genetics, Faculty of Medicine, Afyon Kocatepe University, Afyon, 03200, Turkey
| | - Zeynep Sonmez Celik
- Department of Pulmonary Diseases, Eskisehir State Hospital, Eskisehir, 26060 Turkey
| | - Mehmet Unlu
- Department of Pulmonary Diseases, Faculty of Medicine, Afyon Kocatepe University, Afyon, 03200, Turkey
| | - Mustafa Solak
- Department of Medical Genetics, Faculty of Medicine, Afyon Kocatepe University, Afyon, 03200, Turkey
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NF-kappa B activation correlates with disease phenotype in Crohn's disease. PLoS One 2017; 12:e0182071. [PMID: 28753650 PMCID: PMC5533307 DOI: 10.1371/journal.pone.0182071] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 07/12/2017] [Indexed: 12/22/2022] Open
Abstract
Background/Aims Unregulated activation of nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of Crohn’s disease. In this study, we investigated the clinical characteristics and disease outcome of Crohn’s disease patients with varying levels of the NF-κB activation. Methods Crohn’s disease patients who underwent surgical bowel resection were divided into two groups, based on the activation status of NF-κB. NF-κB activation was assessed by the immunoreactivity of nuclear NF-κB during immunohistochemical staining of bowel resection specimens. We compared the demographic, clinical and histologic characteristics between groups. Furthermore, the occurrence of reoperation, readmission, and medication change due to disease flare-up were investigated according to NF-κB activation status. Results Among 83 Crohn’s disease patients, 47 (56%) showed high NF-κB activity and 36 (44%) showed low NF-κB activity. Patients with high NF-κB activity had higher frequency of ileocolonic involvement (P = 0.028) and lower frequency of perianal involvement (P = 0.042) relative to those with low NF-κB activity. Total histologic scores were significantly higher in patients with high NF-κB activity than those with low NF-κB activity (P = 0.044). There was no significant difference in the frequency of reoperation, readmission, and medication change in relation to NF-κB activation status. Conclusions Crohn’s disease patients with high NF-κB activation showed specific clinical manifestations of higher frequency of ileocolonic involvement and lower frequency of perianal involvement relative to those with low NF-κB activation. High NF-κB activity was associated with higher histologic scores. However, the NF-κB activity did not affect the outcome and disease course after surgery.
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Tolentino YFM, Elia PP, Fogaça HS, Carneiro AJV, Zaltman C, Moura-Neto R, Luiz RR, Carvalho MDGC, de Souza HS. Common NOD2/CARD15 and TLR4 Polymorphisms Are Associated with Crohn's Disease Phenotypes in Southeastern Brazilians. Dig Dis Sci 2016; 61:2636-2647. [PMID: 27107867 DOI: 10.1007/s10620-016-4172-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Accepted: 04/15/2016] [Indexed: 02/07/2023]
Abstract
AIM To investigate whether variants in NOD2/CARD15 and TLR4 are associated with CD and ulcerative colitis (UC) in a genetically admixed population of Rio de Janeiro, where IBD has continued to rise. METHODS We recruited 67 consecutive patients with CD, 61 patients with UC, and 86 healthy and ethnically matched individuals as controls. DNA was extracted from buccal brush samples and genotyped by PCR with restriction enzymes for G908R and L1007finsC NOD2/CARD15 single-nucleotide polymorphisms (SNPs) and for T399I and D299G TLR4 SNPs. Clinical data were registered for subsequent analysis with multivariate models. RESULTS NOD2/CARD15 G908R and L1007finsC SNPs were found in one and three patients, respectively, with CD. NOD2/CARD15 G908R and L1007finsC SNPs were not found in any patients with UC, but were found in three and three controls, respectively. With regard to the TLR4 gene, no significant difference was detected among the groups. Overall, none of the SNPs investigated determined a differential risk for a specific diagnosis. Genotype-phenotype associations were found in only CD, where L1007finsC was associated with colonic localization; however, TLR4 T399I SNP was associated with male gender, and D299G SNP was associated with colonic involvement, chronic corticosteroid use, and the need for anti-TNF-alpha therapy. CONCLUSION Variants of NOD2/CARD15 and TLR4 do not confer susceptibility to IBD, but appear to determine CD phenotypes in this southeastern Brazilian population.
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Affiliation(s)
- Yolanda F M Tolentino
- Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Paula Peruzzi Elia
- Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Homero Soares Fogaça
- Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Antonio José V Carneiro
- Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Cyrla Zaltman
- Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Rodrigo Moura-Neto
- Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-590, Brazil
- Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Duque de Caxias, Rio de Janeiro, 25250-020, Brazil
| | - Ronir Raggio Luiz
- Instituto de Estudos de Saúde Coletiva (IESC), Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21944-970, Brazil
| | - Maria da Gloria C Carvalho
- Laboratório de Patologia Molecular, Departamento de Patologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Heitor S de Souza
- Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil.
- D'Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ, 22281-100, Brazil.
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Verstockt B, Cleynen I. Genetic Influences on the Development of Fibrosis in Crohn's Disease. Front Med (Lausanne) 2016; 3:24. [PMID: 27303667 PMCID: PMC4885006 DOI: 10.3389/fmed.2016.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/13/2016] [Indexed: 12/11/2022] Open
Abstract
Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we review the genetic factors that have been associated with the development of fibrosis in patients with CD, as well as their potential pathophysiological mechanism(s). We also hypothesize on clinical implications, if any, and future research directions.
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Affiliation(s)
- Bram Verstockt
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK; Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven , Leuven , Belgium
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Intestinal fibrosis in Crohn's disease: role of microRNAs as fibrogenic modulators, serum biomarkers, and therapeutic targets. Inflamm Bowel Dis 2015; 21:1141-50. [PMID: 25636122 DOI: 10.1097/mib.0000000000000298] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammation often precedes fibrosis and stricture formation in patients with Crohn's disease. Established medical therapies reduce inflammation, but there are currently no specific therapies to prevent fibrosis or treat established fibrosis. Our understanding of the pathogenic processes underpinning fibrogenesis is limited compared with our knowledge of the events initiating and propagating inflammation. There are several biomarkers for intestinal inflammation, but there are none that reflect the development of fibrosis. MicroRNAs (miRNAs) are regulators of cellular activities including inflammation and fibrosis and may serve as biomarkers of disease processes. Differential serum and mucosal miRNA expression profiles have been identified between patients with inflammatory bowel disease with active and inactive inflammatory disease. In contrast, studies in patients with fibrotic phenotypes are comparatively few, although specific miRNAs have defined roles in the development of fibrosis in other organ systems. Here, we discuss the most recent research on miRNA and fibrogenesis with a particular emphasis on Crohn's disease. We also anticipate the potential of miRNAs in fulfilling current unmet translational needs in this patient group by focusing on the role of miRNAs as modulators of fibrogenesis and on their potential value as serum biomarkers and therapeutic targets in the management of fibrosis.
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Branković I, van Ess EF, Noz MP, Wiericx WAJ, Spaargaren J, Morré SA, Ouburg S. NOD1 in contrast to NOD2 functional polymorphism influence Chlamydia trachomatis infection and the risk of tubal factor infertility. Pathog Dis 2015; 73:1-9. [PMID: 25854006 DOI: 10.1093/femspd/ftu028] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2014] [Indexed: 01/01/2023] Open
Abstract
Intracellular pattern-recognition receptors NOD1 and NOD2 are capable of sensing common structural units of bacterial walls. Recognition triggers specific immune signalling pathways and leads to pro-inflammatory cytokine upregulation and adequate immune response. We investigated whether two functional polymorphisms in NOD1 and NOD2 exert an effect on susceptibility to (STD patients) and severity of (female patients visiting the fertility clinic) Chlamydia trachomatis infection in 807 Dutch Caucasian women. A significant association of the NOD1 +32656 GG insertion variant with protection against infection with C. trachomatis has been detected [p: 0.0057; OR: 0.52]. When comparing C. trachomatis-positive women without symptoms to C. trachomatis-positive women with symptoms, and to C. trachomatis-positive women with TFI, we observed an increasing trend in carriage of the GG allele [Ptrend: 0.0003]. NOD2 1007fs failed to reveal an association. We hypothesize that the underlying mechanism might be a functional effect of the GG insertion on IFN-beta-dependent regulation of immune response in the genital tract. The research is part of an ongoing effort of identifying key polymorphisms that determine the risk of TFI and effectively translating them into the clinical setting for the purpose of optimizing diagnostic management of women at risk for developing TFI.
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Affiliation(s)
- Ivan Branković
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands Institute for Public Health Genomics, Department of Genetics and Cell Biology, School for Oncology and Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Eleanne F van Ess
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Marlies P Noz
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Wilhelmina Anke J Wiericx
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Joke Spaargaren
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Servaas A Morré
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands Institute for Public Health Genomics, Department of Genetics and Cell Biology, School for Oncology and Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands Dutch Chlamydia trachomatis Reference Laboratory, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Sander Ouburg
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
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Bao R, Huang L, Andrade J, Tan W, Kibbe WA, Jiang H, Feng G. Review of current methods, applications, and data management for the bioinformatics analysis of whole exome sequencing. Cancer Inform 2014; 13:67-82. [PMID: 25288881 PMCID: PMC4179624 DOI: 10.4137/cin.s13779] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 07/06/2014] [Accepted: 07/07/2014] [Indexed: 12/21/2022] Open
Abstract
The advent of next-generation sequencing technologies has greatly promoted advances in the study of human diseases at the genomic, transcriptomic, and epigenetic levels. Exome sequencing, where the coding region of the genome is captured and sequenced at a deep level, has proven to be a cost-effective method to detect disease-causing variants and discover gene targets. In this review, we outline the general framework of whole exome sequence data analysis. We focus on established bioinformatics tools and applications that support five analytical steps: raw data quality assessment, pre-processing, alignment, post-processing, and variant analysis (detection, annotation, and prioritization). We evaluate the performance of open-source alignment programs and variant calling tools using simulated and benchmark datasets, and highlight the challenges posed by the lack of concordance among variant detection tools. Based on these results, we recommend adopting multiple tools and resources to reduce false positives and increase the sensitivity of variant calling. In addition, we briefly discuss the current status and solutions for big data management, analysis, and summarization in the field of bioinformatics.
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Affiliation(s)
- Riyue Bao
- Center for Research Informatics, The University of Chicago, Chicago, IL, USA
| | - Lei Huang
- Center for Research Informatics, The University of Chicago, Chicago, IL, USA
| | - Jorge Andrade
- Center for Research Informatics, The University of Chicago, Chicago, IL, USA
| | - Wei Tan
- IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA
| | - Warren A Kibbe
- Biomedical Informatics Center (NUBIC), Clinical and Translational Sciences Institute (NUCATS), Northwestern University, Chicago, IL, USA
| | - Hongmei Jiang
- Department of Statistics, Northwestern University, Evanston, IL, USA
| | - Gang Feng
- Biomedical Informatics Center (NUBIC), Clinical and Translational Sciences Institute (NUCATS), Northwestern University, Chicago, IL, USA
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Bhullar M, Macrae F, Brown G, Smith M, Sharpe K. Prediction of Crohn’s disease aggression through NOD2/ CARD15 gene sequencing in an Australian cohort. World J Gastroenterol 2014; 20:5008-5016. [PMID: 24803813 PMCID: PMC4009534 DOI: 10.3748/wjg.v20.i17.5008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/04/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.
METHODS: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene.
RESULTS: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020insC of the NOD2/CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2/CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries.
CONCLUSION: These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn’s disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.
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NOD2 Polymorphisms and Their Impact on Haematopoietic Stem Cell Transplant Outcome. BONE MARROW RESEARCH 2012; 2012:180391. [PMID: 23119165 PMCID: PMC3483648 DOI: 10.1155/2012/180391] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 09/03/2012] [Indexed: 12/17/2022]
Abstract
Haematopoietic stem cell transplantation (HSCT) is a valuable tool in the treatment of many haematological disorders. Advances in understanding HLA matching have improved prognoses. However, many recipients of well-matched HSCT develop posttransplant complications, and survival is far from absolute. The pursuit of novel genetic factors that may impact on HSCT outcome has resulted in the publication of many articles on a multitude of genes. Three NOD2 polymorphisms, identified as disease-associated variants in Crohn's disease, have recently been suggested as important candidate gene markers in the outcome of HSCT. It was originally postulated that as the clinical manifestation of inflammatory responses characteristic of several post-transplant complications was of notable similarity to those seen in Crohn's disease, it was possible that they shared a common cause. Since the publication of this first paper, numerous studies have attempted to replicate the results in different transplant settings. The data has varied considerably between studies, and as yet no consensus on the impact of NOD2 SNPs on HSCT outcome has been achieved. Here, we will review the existing literature, summarise current theories as to why the data differs, and suggest possible mechanisms by which the SNPs affect HSCT outcome.
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Brinar M, Vermeire S, Cleynen I, Lemmens B, Sagaert X, Henckaerts L, Van Assche G, Geboes K, Rutgeerts P, De Hertogh G. Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients. J Crohns Colitis 2012; 6:43-50. [PMID: 22261526 DOI: 10.1016/j.crohns.2011.06.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 05/31/2011] [Accepted: 06/19/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation. METHODS Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes. RESULTS Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163). CONCLUSION These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation.
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Affiliation(s)
- Marko Brinar
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
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Almadi MA, Aljebreen AM, Sanai FM, Marcus V, Almeghaiseeb ES, Ghosh S. New insights into gastrointestinal and hepatic granulomatous disorders. Nat Rev Gastroenterol Hepatol 2011; 8:455-66. [PMID: 21818145 DOI: 10.1038/nrgastro.2011.115] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Numerous diseases that involve the gastrointestinal tract reveal the presence of granulomas on histological analysis. Granulomatous diseases can be either primary or secondary to environmental factors. Granulomas are dynamic structures composed of organized collections of activated macrophages, including epithelioid and multinucleated giant cells, surrounded by lymphocytes. The formation of granulomas is usually in response to antigenic stimulation and is orchestrated through cytokines, immune cells and host genetics. In this Review, the pathogenesis and etiologies of granulomas of the gastrointestinal tract and liver are discussed, as are the available diagnostic tools to help differentiate their various underlying etiologies. In addition, the role of granulomas in harboring latent tuberculosis is reviewed. The effects of tumor necrosis factor antagonists and interferon-α on the development of granulomas are also discussed.
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Affiliation(s)
- Majid A Almadi
- Department of Medicine, Gastroenterology Division, King Khalid University Hospital, King Saud University, PO Box 231494, Riyadh 11321, Saudi Arabia.
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Abstract
OBJECTIVES Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease. METHODS An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years). RESULTS The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95% CI) 1.10-1.24; P<0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95% CI 1.11-1.60; P=0.002). NOD2 did not predict perianal disease (P=0.4). The RR of surgery was 1.58 (95% CI 1.38-1.80; P<0.001). There was substantial heterogeneity across all studies (I(2)=66.7%). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73%, with the area under the receiver operating characteristic curve 0.56. CONCLUSIONS The presence of a single NOD2 mutation predicted an 8% increase in the risk for complicated disease (B2 or B3), and a 41% increase with 2 mutations. Surgery risk is increased by 58% with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17% across 36 studies. However, the presence of two NOD2 mutations had 98% specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.
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Abstract
PURPOSE Pouchitis and Crohn's-like complications can plague patients after IPAA. NOD2 is an intracellular sensor for bacterial cell wall peptidoglycan. NOD2 mutations compromise host response to enteric bacteria and are increased in Crohn's disease. We hypothesize that IPAA patients with complications (Crohn's disease-like/pouchitis) have a higher rate of NOD2 mutations compared with asymptomatic IPAA patients. METHODS Patients were retrospectively subclassified into the following groups: 1) IPAA with Crohn's-like complications (n = 28, perianal fistula, pouch inlet stricture/upstream small-bowel disease, or biopsies showing granulomata) occurring at least 6 months after ileostomy closure; 2) IPAA with mild pouchitis (n = 33, ≤3 episodes/y for 2 consecutive years); 3) IPAA with severe pouchitis (n = 9, ≥4 episodes/y for 2 consecutive years or need for continuous antibiotics); 4) IPAA without complications or pouchitis (n = 37); 5) patients with Crohn's disease with colitis undergoing total proctocolectomy/ileostomy (n = 11); and 6) healthy controls (n = 269). The 3 NOD2 single-nucleotide polymorphism mutations (rs2066844, rs2066845, and rs2066847) previously identified as associated with Crohn's disease were genotyped using polymerase chain reaction. Groups were compared by use of χ with Yates continuity correction. RESULTS NOD2 mutations were found in 8.5% of healthy controls. NOD2 mutations were significantly higher in the severe pouchitis group (67%) compared with both asymptomatic IPAA (5.4%, P < .001) and IPAA with Crohn's disease-like complications (14.3%, P = .008) groups. CONCLUSIONS 1) Asymptomatic IPAA patients have a low incidence of NOD2 mutations not significantly different from patients with mild pouchitis or healthy controls. 2) Patients with severe pouchitis had the highest incidence of NOD2 mutations, suggesting that this group may have a compromised host defense mechanism to enteric bacteria. 3) Patients with Crohn's-like complications after IPAA have a significantly lower incidence of NOD2 mutations than patients with severe pouchitis, suggesting a different genetic makeup in these 2 patient groups. Preoperative assessment of NOD2 in the equivocal IPAA candidate may predict severe pouchitis and might assist in preoperative surgical decision making.
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Abstract
OBJECTIVES The aim of this study was to evaluate any potential influence of a family history of inflammatory bowel disease (IBD) on the clinical phenotypes and the course of IBD in children. METHODS In this retrospective study, the notes of 411 children with the diagnosis of IBD, 244 (59.4%) with ulcerative colitis, 129 (31.4%) with Crohn's disease and 38 (9.2%) with IBD unclassified, who were admitted to our department between 1 January 1981 and 31 December 2007 were reviewed. The aim was to assess the prevalence of familial IBD and its impact on the age of disease onset, clinical phenotypes according to the Montreal classification, course and outcome of disease. The control group consisted of IBD children without a family history of IBD, who were admitted to the hospital during the same time period. RESULTS Thirty five (8.5%) children had a family history of IBD, (ulcerative colitis 6.6%, Crohn's disease 10.9% and IBD unclassified 13.2%). Sixty-eight percent of the 22 pairs of first-degree relatives were concordant for the clinical phenotype of disease. Significantly, more children with familial IBD had symptom onset and/or disease diagnosis before 5 years of age compared with sporadic IBD (P = 0.01 and P = 0.014, respectively); however, no differences were seen in sex, clinical phenotypes, need for aggressive treatment and/or surgery. CONCLUSION Children with familial IBD had earlier onset of disease compared with those with sporadic IBD. However, this had no significant impact on the clinical phenotypes, the course and/or the outcome of disease.
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Abstract
Technological advances in genomics and transcriptomics have resulted in the introduction of molecular tests into the clinical arena. Despite established uses of such tests in the oncology field, their integration into the management of complex diseases has not been widely evaluated. Progress in the field of inflammatory bowel disease (IBD) genetics has been rapid in recent years, and these advances have provided more urgent impetus to investigating the role of molecular tests in IBD. This article summarizes the current state of molecular testing available for IBD, and the potential utility of such tests as research in the area widens.
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Diminution of Circulating CD4+CD25 high T cells in naïve Crohn's disease. Dig Dis Sci 2009; 54:2084-93. [PMID: 19051021 DOI: 10.1007/s10620-008-0590-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Accepted: 10/17/2008] [Indexed: 12/13/2022]
Abstract
Crohn's disease is considered to be caused either by an excess of T-cell effector functions and/or by a defective regulatory T-cell compartment. The aim of this study was to assess in Crohn's disease the frequency of circulating CD4(+)CD25(high) T cells that possess regulatory T-cell functions and CD4(+)CD25(low) T cells that contain activated T cells. Flow cytometry of peripheral blood was used to assess CD4(+)CD25(high) and CD4(+)CD25(low) T-cell frequencies in a cohort of 66 patients with Crohn's disease in comparison to 19 patients with ulcerative colitis and 31 healthy individuals enrolled as controls. The CD4(+)CD25(high) T-cell frequency was significantly lowered in naïve Crohn's disease (P = 0.013) and in ulcerative colitis (P = 0.001). CD4(+)CD25(low) T-cell frequency was increased in Crohn's disease (P = 0.0001) and in ulcerative colitis (P = 0.0002). Both CD4(+)CD25(high) and CD4(+)CD25(low) T-cell frequencies are altered in naïve Crohn's disease resulting in an imbalance between both populations and a relative contraction of the CD4(+)CD25(high) T-cell population.
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Yazdanyar S, Weischer M, Nordestgaard BG. Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis. Clin Chem 2009; 55:1950-7. [PMID: 19713276 DOI: 10.1373/clinchem.2009.127126] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. METHODS We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally important risk factors for Crohn disease. In addition, we used studies for which combined information from all genotypes was available to compare risks in simple heterozygotes, compound heterozygotes, and homozygotes. PubMed, EMBASE, and Web of Science were searched. Seventy-five articles (18 727 cases and 17 102 controls) met the inclusion criteria and contributed data to the metaanalyses. RESULTS The odds ratios per allele for Crohn disease were 2.2 (95% CI, 2.0-2.5) for Arg702Trp, 2.6 (2.2-2.9) for Gly908Arg, and 3.8 (3.4-4.3) for Leu1007fsinsC (z-test results: Arg702Trp vs Gly908Arg, P = 0.03; Arg702Trp vs Leu1007fsinsC, P < 0.001; Gly908Arg vs Leu1007fsinsC, P < 0.001). When all 3 genotypes were combined, odds ratios for Crohn disease were 2.4 (95% CI, 2.0-2.8) for simple heterozygotes, 9.0 (6.0-13.5) for compound heterozygotes, and 6.7 (4.1-10.9) for homozygotes, compared with noncarriers (z-test results: simple heterozygotes vs compound heterozygotes, P < 0.001; simple heterozygotes vs homozygotes, P < 0.001; compound heterozygotes vs homozygotes, P = 0.18). CONCLUSIONS The per-allele risk of Crohn disease was markedly higher for Leu1007fsinsC than for Arg702Trp and Gly908Arg. Combining all genotypes revealed the risks of Crohn disease for compound heterozygotes and homozygotes to be similar and markedly higher than for simple heterozygotes.
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Affiliation(s)
- Shiva Yazdanyar
- Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen DK-2730, Denmark
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Chua KH, Hilmi I, Ng CC, Eng TL, Palaniappan S, Lee WS, Goh KL. Identification of NOD2/CARD15 mutations in Malaysian patients with Crohn's disease. J Dig Dis 2009; 10:124-30. [PMID: 19426395 DOI: 10.1111/j.1751-2980.2009.00374.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The NOD2/CARD15 gene has been identified as an important susceptibility gene for Crohn's disease (CD) but the three common disease predisposing mutations (DPM) found in developed countries have not been identified in Asian populations. The aim of our study was to look for the DPM in our multiracial population and to discover whether there were any differences in the three major ethnic groups; Malay, Chinese and Indian. METHODS Blood samples from consecutive CD patients and healthy controls were obtained and analyzed for the three common mutations (R702W, G908R, 1007fs) but in addition to this, we also looked for the SNP5 and JW1 variants which are associated with CD in Ashkenazi Jews. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to identify the mutations, which was confirmed by sequencing. The baseline socio-demography and clinical characteristics of the CD patients were recorded. RESULTS Overall 45 patients (three Malays, 15 Chinese, 26 Indians and one other) with confirmed CD and 300 controls were recruited. The three common DPM were not observed in either the CD patients or the controls. Neither the SNP5 nor the JW1 mutation was found in any of the controls. However, the SNP5 mutation was identified in six (13.3%) Indian CD patients and the JW1 mutation in eight CD patients who are different from those carrying the SNP5 mutation: one Malay (33.3%), two Chinese (13.3%), one other (Portuguese) and four Indians (15.4%). The presence of SNP5 was strongly associated with CD in the Indian population and that of JW1 was strongly associated with CD overall and in each of the major ethnic groups. There was a trend towards a younger age of onset and stricturing disease in patients carrying the JW1 mutation. CONCLUSION These findings suggest the presence of novel DPM in the NOD2/CARD15 gene in Asian patients with CD.
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Affiliation(s)
- Kek Heng Chua
- Department of Molecular Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Sabate JM, Ameziane N, Lamoril J, Jouet P, Farmachidi JP, Soulé JC, Harnois F, Sobhani I, Jian R, Deybach JC, de Prost D, Coffin B. The V249I polymorphism of the CX3CR1 gene is associated with fibrostenotic disease behavior in patients with Crohn's disease. Eur J Gastroenterol Hepatol 2008; 20:748-55. [PMID: 18617779 DOI: 10.1097/meg.0b013e3282f824c9] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES CX3CR1, the receptor of CX3CL1/fractalkine, is involved in regulation of inflammatory response and the CX3CR1-I249-M280 naturally occurring mutants are associated with altered binding to the ligand. Our aim was to evaluate the frequency of CX3CR1 V249I and T280M polymorphisms and NOD2/CARD15 mutations in Crohn's disease patients and to search for a relationship with phenotype. METHODS Clinical data were retrospectively collected. V249I and T280M polymorphisms of CX3CR1 gene and NOD2/CARD15 mutations (R702W, G908R, 3020InsC) were identified. RESULTS Two hundred and thirty-nine patients (140 females, 39.7+/-14.1 years) were included. About 37.4% were heterozygous and 8.8% were homozygous for the V249I CX3CR1 polymorphism, 18.1% were heterozygous and 1.3% homozygous for the T280M CX3CR1 polymorphism and 35.9% had at least one of the three mutations of NOD2/CARD15. The T280M CX3CR1 polymorphism was not associated with any phenotype. In univariate analysis, stenosis was significantly associated with both V249I CX3CR1 polymorphism and 3020InsC NOD2/CARD15 mutations. In smoker patients carrying the CX3CR1 allele I249, there was a significant increase in the frequency of fibrostenosing disease [P=0.005, odds ratio (OR): 3.25] whereas this relationship disappeared in the group of nonsmokers (P=0.72). In multivariate analysis, 3020InsC NOD2/CARD15 mutations and the V249I CX3CR1 polymorphism were independent risk factors for intestinal stenosis (P=0.046, OR: 1.8 and P=0.044, OR: 2.4, respectively). CONCLUSION In Crohn's disease, V249I CX3CR1 polymorphism is associated with intestinal strictures, particularly in smokers. This association is independent of CARD15 mutations.
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Affiliation(s)
- Jean-Marc Sabate
- Department of Gastroenterology and Hepatology, AP-HP, Louis Mourier Hospital, Colombes, France
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Abstract
BACKGROUND Granulomas are pathognomonic findings of Crohn disease (CD); however, their occurrence and clinical significance are not well characterized. Our aim was to determine the frequency and distribution of granulomas in untreated and treated patients with CD and their relation to age and disease severity. PATIENTS AND METHODS Records from patients with CD undergoing colonoscopy with terminal ileum biopsy over 7 years were reviewed. Clinical information and laboratory, pathology, and radiology results were recorded. The frequency and distribution of granulomas were determined. RESULTS From 376 patients with CD, 75% underwent concurrent esophagogastroduodenoscopy and colonoscopy. Of those, 65% (184/282) were untreated. Granulomas were identified in 48% (136/282) of all patients and in 61% (112/184) of untreated patients and 24.5% (24/98) of treated patients (P < 0.0005). The upper tract and terminal ileum biopsies were essential to the identification of 42% of patients with granulomas. The presence of granulomas at diagnosis was related to anti-Saccharomyces cerevisiae antibodies, hypoalbuminemia, perianal disease, and gastritis at presentation (P = 0.03, P = 0.008, P = 0.03, and P = 0.001), respectively, and to perianal disease and infliximab treatment at the latest visit (P = 0.02 and P = 0.01), respectively. Granulomas were not related to age, sex, ethnicity, weight and height z scores, hemoglobin, C-reactive protein, erythrocyte sedimentation rate, CARD15/NOD2 mutations, abdominal surgery, or stricturing or fistulizing disease. CONCLUSIONS Granulomas were identified in 61% of fully investigated pediatric patients with CD at diagnosis, including a substantial proportion of patients in whom colonoscopy to the cecum would have been insufficient for diagnosis. Granulomas were more frequent in untreated patients (P < 0.0005), and their prevalence was not affected by age. The presence of granulomas at diagnosis was associated with perianal disease, gastritis, hypoalbuminemia, anti-Saccharomyces cerevisiae antibodies, and infliximab treatment.
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Chow DKL, Leong RWL, Lai LH, Wong GLH, Leung WK, Chan FKL, Sung JJY. Changes in Crohn's disease phenotype over time in the Chinese population: validation of the Montreal classification system. Inflamm Bowel Dis 2008; 14:536-41. [PMID: 18058793 DOI: 10.1002/ibd.20335] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Phenotypic evolution of Crohn's disease occurs in whites but has never been described in other populations. The Montreal classification may describe phenotypes more precisely. The aim of this study was to validate the Montreal classification through a longitudinal sensitivity analysis in detecting phenotypic variation compared to the Vienna classification. METHODS This was a retrospective longitudinal study of consecutive Chinese Crohn's disease patients. All cases were classified by the Montreal classification and the Vienna classification for behavior and location. The evolution of these characteristics and the need for surgery were evaluated. RESULTS A total of 109 patients were recruited (median follow-up: 4 years, range: 6 months-18 years). Crohn's disease behavior changed 3 years after diagnosis (P = 0.025), with an increase in stricturing and penetrating phenotypes, as determined by the Montreal classification, but was only detected by the Vienna classification after 5 years (P = 0.015). Disease location remained stable on follow-up in both classifications. Thirty-four patients (31%) underwent major surgery during the follow-up period with the stricturing [P = 0.002; hazard ratio (HR): 3.3; 95% CI: 1.5-7.0] and penetrating (P = 0.03; HR: 5.8; 95% CI: 1.2-28.2) phenotypes according to the Montreal classification associated with the need for major surgery. In contrast, colonic disease was protective against a major operation (P = 0.02; HR: 0.3; 95% CI: 0.08-0.8). CONCLUSIONS This is the first study demonstrating phenotypic evolution of Crohn's disease in a nonwhite population. The Montreal classification is more sensitive to behavior phenotypic changes than is the Vienna classification after excluding perianal disease from the penetrating disease category and was useful in predicting course and the need for surgery.
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Affiliation(s)
- Dorothy K L Chow
- Institute of Digestive Disease, Chinese University of Hong Kong, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong.
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Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease. Eur J Gastroenterol Hepatol 2008; 20:37-45. [PMID: 18090989 DOI: 10.1097/meg.0b013e3282f1622b] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Genetic variants at the CARD15 and IBD5 loci are strongly associated with Crohn's disease (CD), but evidence of the effect of these variants on the clinical expression of CD is conflicting and has often been hampered by small sample sizes. We studied 630 well-characterized patients to clarify the genotype/phenotype relationship in CD. METHODS Patients and healthy controls were genotyped for three common mutations in CARD15 and a marker of the IBD5 risk haplotype. Allele frequencies were compared between phenotypic subgroups using chi2 or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors. RESULTS The mean age at diagnosis was significantly lower in carriers of the CARD15 or IBD5 risk alleles. After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease. CARD15 mutations were also associated with the presence of granulomas (P=5.7 x 10(-5)), which remained significant after adjustment for age at diagnosis and disease location (P=0.0047). The IBD5 risk haplotype frequency was significantly elevated in cases with perianal disease (P=0.028) and axial spondyloarthropathy (P=0.012). CONCLUSION Genetic variants at the CARD15 and IBD5 loci have diverse effects on clinical expression in CD. CARD15 mutations are significantly correlated with the presence of granulomas.
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Hugot JP, Zaccaria I, Cavanaugh J, Yang H, Vermeire S, Lappalainen M, Schreiber S, Annese V, Jewell DP, Fowler EV, Brant SR, Silverberg MS, Cho J, Rioux JD, Satsangi J, Parkes M. Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol 2007; 102:1259-1267. [PMID: 17319929 DOI: 10.1111/j.1572-0241.2007.01149.x] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Crohn's disease (CD) has been associated with CARD15/NOD2 mutations in Caucasians. The R702W, G908R, and 1007fs mutations represent 82% of the mutated chromosomes. The relative risk of developing CD in homozygous or compound heterozygous people has been estimated as between 10 and 40 times that of the general population. This high risk may support the opinion that CARD15/NOD2 variants are strong CD risk factors at the individual and population levels. SUBJECTS AND METHODS The allele and genotype frequencies were calculated for the R702W, G908R, and 1007fs mutations in 3,575 Caucasian healthy controls recruited by 15 groups distributed on three continents. Geographic homogeneity was tested and the observed proportion of double mutants was compared with the expected value using chi2 tests. RESULTS The allele frequencies of the R702W, G908R, and 1007fs mutations were 4.3% (3.6-4.9), 1.2% (0.8-1.6), and 2.3% (1.8-2.8), respectively, with large geographic fluctuations of the G908R, 1007fs, and wild-type alleles (P<0.0001). At the population level, no simple relationship was observed between mutation frequencies and the disease incidences in the studied populations. At the individual level, no significant deficit of double-dose mutation carriers among healthy controls was found, providing strong evidence that the penetrances of the most at-risk genotypes are low. CONCLUSION Altogether, these data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors.
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Affiliation(s)
- Jean-Pierre Hugot
- INSERM Avenir U763; AP-HP; Université Paris 7, Hôpital Robert Debré, Paris, France
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van der Linde K, Boor PPC, Houwing-Duistermaat JJ, Crusius BJA, Wilson PJH, Kuipers EJ, de Rooij FWM. CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies. Eur J Gastroenterol Hepatol 2007; 19:449-59. [PMID: 17489054 DOI: 10.1097/01.meg.0000236887.44214.6a] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. METHODS Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. RESULTS In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P>or=0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). CONCLUSION In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.
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Affiliation(s)
- Klaas van der Linde
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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Bianchi V, Maconi G, Ardizzone S, Colombo E, Ferrara E, Russo A, Tenchini ML, Porro GB. Association of NOD2/CARD15 mutations on Crohn's disease phenotype in an Italian population. Eur J Gastroenterol Hepatol 2007; 19:217-23. [PMID: 17301648 DOI: 10.1097/01.meg.0000250590.84102.12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIMS To confirm the prevalence of NOD2/CARD15 mutations in Italian inflammatory bowel disease patients and to define the role of the different mutations on Crohn's disease phenotype. PATIENTS AND METHODS A total of 177 patients with Crohn's disease and 92 patients with ulcerative colitis and 164 control participants were investigated for the presence of Arg702Trp, Gly908Arg and Leu1007fsinsC NOD2/CARD15 mutations. Allele frequencies in Crohn's disease and ulcerative colitis patients were compared with those observed in the control population. Genotype-phenotype correlations with the major clinical features were also established and estimated risks (odds ratio with 95% confidence interval) for the mutations were calculated by logistic regression and multiple correspondent analysis. RESULTS Gly908Arg and Leu1007fsinsC mutations were significantly more frequent in Crohn's disease patients compared with healthy controls (P<0.01 and <0.003 respectively). Indeed, using a logistic regression model adding terms for age (differently distributed between cases and controls) and sex, a significantly increased risk of having Crohn's disease compared with healthy controls was found for all NOD2 mutations: Leu1007fsinsC (odds ratio=7.35; 95% confidence interval: 1.73-31.3), Gly908Arg (odds ratio=5.70; 95% confidence interval: 1.37-23.7) and Arg702Trp (odds ratio=2.45; 95% confidence interval: 1.10-5.47). As far as the genotype-phenotype correlations are concerned, by multivariate conditional logistic regression methods, we found a significant association between Gly908Arg mutations and familial history of inflammatory bowel disease, between Leu1007fsinsC mutations and appendectomy and between Arg702Trp mutations and fibrostenotic phenotype of Crohn's disease. A nonsignificant association between Arg702Trp variants and ileal disease was also found (odds ratio=8, 95% confidence interval: 0.99-64.9). CONCLUSIONS The results of the study confirm a significant association of CARD15 gene mutations in our Italian Crohn's disease population and the impact of different NOD2/CARD15 mutations on specific disease phenotypes.
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Affiliation(s)
- Vera Bianchi
- Department of Biology and Genetics for Medical Sciences, University of Milan, Italy
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Brant SR, Wang MH, Rawsthorne P, Sargent M, Datta LW, Nouvet F, Shugart YY, Bernstein CN. A population-based case-control study of CARD15 and other risk factors in Crohn's disease and ulcerative colitis. Am J Gastroenterol 2007; 102:313-23. [PMID: 17100976 DOI: 10.1111/j.1572-0241.2006.00926.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Multiple established Crohn's disease (CD) and ulcerative colitis (UC) risk factors including family history, tobacco use, Jewish ethnicity, urban residency, and CARD15/NOD2 mutations have been evaluated singly and in hospital-based observational studies. The goal of this study was to assess the relative contributions of all these risk factors jointly in a nonreferral, population-based cohort derived from a population epidemiologic database. METHODS CD (N = 232) and UC (N = 121) subjects were ascertained from our population-based IBD Registry derived from Manitoba Health, the single provincial insurer. Healthy controls (HC) (N = 336) were recruited via a 10:1 mailing matched for age, sex, and postal code. Ethnicity, tobacco use, family history, residency, and CARD15/NOD2 genotype status were determined. RESULTS In both univariate analyses and analyses adjusted for all risk factors, CD was influenced independently by CARD15/NOD2 heterozygote and homozygote/compound-heterozygote status (adjusted odds ratios [OR] 3.7 and 40.0, respectively), Jewish ethnicity (OR 18.5), CD family history (OR 6.2), and smoking (OR 3.0 current and 1.7 ex-smoker, respectively). Penetrance for homozygote/compound-heterozygotes was 4.9%, heterozygotes 0.54%, and wild types 0.184%. Population attributable risk for CARD15 was 26.7% and current tobacco use was 46.8%. A tobacco-CARD15 interaction was not observed. UC was influenced by Jewish ethnicity (OR 37.1), and by family history (OR 2.6), ex-smoker status (OR 1.9), and CARD15/NOD2 heterozygote or homozygote/compound-heterozygote status (OR 1.9 and 6.4, respectively) in adjusted analyses only. CONCLUSIONS CARD15/NOD2, family history, smoking, and Jewish ethnicity are independent risk factors for CD. Examination of these risk factors together in a single population-based cohort has provided initial data for population epidemiological characterization and genetic counseling uses.
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Affiliation(s)
- Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Walters TD, Silverberg MS. Genetics of inflammatory bowel disease: current status and future directions. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 20:633-9. [PMID: 17066152 PMCID: PMC2660789 DOI: 10.1155/2006/326025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Thomas D Walters
- Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario
| | - Mark S Silverberg
- Department of Medicine, Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario
- Correspondence: Dr Mark S Silverberg, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Room 441, 600 University Avenue, Toronto, Ontario M5G 1X5. Telephone 416-586-8236, fax 416-586-4878, e-mail
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Dambacher J, Staudinger T, Seiderer J, Sisic Z, Schnitzler F, Pfennig S, Hofbauer K, Konrad A, Tillack C, Otte JM, Diebold J, Göke B, Ochsenkühn T, Lohse P, Brand S. Macrophage migration inhibitory factor (MIF) -173G/C promoter polymorphism influences upper gastrointestinal tract involvement and disease activity in patients with Crohn's disease. Inflamm Bowel Dis 2007; 13:71-82. [PMID: 17206642 DOI: 10.1002/ibd.20008] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with increased expression in inflammatory bowel disease. The aim of the study was to analyze the role of the MIF -173G/C single nucleotide polymorphism in Crohn's disease (CD). METHODS Using restriction fragment length polymorphism analysis, genomic DNA of 198 patients with CD and 159 unrelated controls was analyzed for the -173G/C SNP in the MIF promoter region. Colonic MIF mRNA expression was measured by quantitative polymerase chain reaction (PCR), serum MIF levels by enzyme-linked immunosorbent assay (ELISA). RESULTS Thirty-six of the 146 G/G wildtype carriers (24.7%) but only 3 of the 45 G/C heterozygotes (6.7%) and only 1 of the C/C homozygotes (14.3%) were diagnosed with upper gastrointestinal tract involvement (P = 0.009, odds ratio [OR] = 0.22, 95% confidence interval [CI], 0.06-0.75 for wildtype versus hetero- and homozygous carriers). This result was confirmed in a second prospective study, in which all patients diagnosed with upper gastrointestinal involvement (n = 13) were G/G wildtype carriers (P = 0.01 versus controls). All patients (n = 12; 100%) with a Crohn's disease activity index (CDAI) > 300 were G/G wildtype carriers compared to only 65.6% wildtype carriers in the group with a CDAI < 150 (P = 0.016). MIF is expressed in the colonic mucosa of CD patients and intestinal epithelial cells but its mRNA expression does not correlate with the degree of inflammation and is not upregulated by proinflammatory cytokines. In CD, MIF serum levels are not influenced by the MIF -173G/C polymorphism. CONCLUSIONS The MIF -173G/C polymorphism appears to be a factor contributing to a particular CD phenotype characterized by protection against upper gastrointestinal tract involvement and severe disease activity.
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Affiliation(s)
- Julia Dambacher
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
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Radford-Smith G, Pandeya N. Associations between NOD2/CARD15 genotype and phenotype in Crohn’s disease-Are we there yet? World J Gastroenterol 2006; 12:7097-103. [PMID: 17131470 PMCID: PMC4087769 DOI: 10.3748/wjg.v12.i44.7097] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There have been multiple NOD2/CARD15 genotype-phenotype analyses undertaken in patients with Crohn's disease since the gene’s discovery in 2001. This review focuses on the major published series based upon their size and on the presence of specific clinical and genetic information provided in the published material from 2001 to 2005. Twelve studies provided raw data to carry out comparisons of disease location while ten studies included analysis of NOD2/CARD15 genotypes. NOD2/CARD15 variant frequency in ileal disease did not differ significantly among studies, whereas a comparison of disease location demonstrated highly significant differences among studies. Meta-analysis confirmed significant associations between NOD2/CARD15 variants and both ileal and ileocolonic disease locations, and with both stricturing and penetrating forms of disease behavior. This review underlines the significant phenotypic differences that exist among populations, including similar ethnic groups, and has demonstrated the need for further studies of patients with long-term “inflammatory” Crohn’s disease.
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Affiliation(s)
- Graham Radford-Smith
- IBD Unit, Department of Gastroenterology, Royal Brisbane and Womens Hospital, Brisbane, Queensland 4029, Australia.
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De Diego C, Alcántara M, Valle J, Pérez-Grueso MJ, Muñoz-Rosas C, Carrobles JM, Martínez-Castro P. Frequency of CARD15 Polymorphisms in Patients with Crohn's Disease from Toledo, Spain: Genotype–Phenotype Correlation. ACTA ACUST UNITED AC 2006; 10:178-85. [PMID: 17020469 DOI: 10.1089/gte.2006.10.178] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Crohn's disease (CD) presents a complex multifactorial etiology with genetic and environmental factors contributing to the disorder. Epidemiological studies have shown that three major CARD15 polymorphisms, R702W, G908R, and 1007fs, are associated with CD. We studied the frequencies of these three polymorphisms in patients from Toledo, Spain, and compared them with the frequencies found in studies of other populations. A total of 183 patients with CD and 172 healthy controls from Toledo, Spain, were included in this study. All of these individuals were genotyped for the three CARD15 polymorphisms R702W, G908R, and 1007fs. Frequencies were analyzed to identify any genotype-phenotype associations. The control population exhibited frequencies of CARD15 polymorphisms similar to the results of previous studies, 3.4%, 1.1%, and 2.0% for the R702W, G908R, and 1007fs polymorphisms, respectively, whereas CD patients had allele frequencies of 7.6%, 3.0%, and 4.6%, respectively. Significant associations were found between the presence of R702W and patients carrying two susceptibility variants with early age of onset and stricturing pattern.
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Affiliation(s)
- Carles De Diego
- Department of Genetics, Hospital Virgen de la Salud, Toledo, Spain.
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Cukovic-Cavka S, Vermeire S, Hrstic I, Claessens G, Kolacek S, Jakic-Razumovic J, Krznaric Z, Grubelic K, Radic D, Misak Z, Jadresin O, Rutgeerts P, Vucelic B. NOD2/CARD15 mutations in Croatian patients with Crohn's disease: prevalence and genotype-phenotype relationship. Eur J Gastroenterol Hepatol 2006; 18:895-9. [PMID: 16825909 DOI: 10.1097/00042737-200608000-00016] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with variations in localization and behaviour. Mutations in the NOD2/CARD15 gene on chromosome 16q have been implicated in the pathogenesis of the disease and three main sequence variants, all single nucleotide polymorphisms (SNPs), have been identified in North American and European populations. AIMS AND METHODS As no data exist in the Croatian population, we consecutively collected a cohort of 136 CD patients and 91 healthy controls to determine the prevalence of NOD2/CARD15 mutations and their association with phenotypic expression of the disease. All patients and controls were genotyped for Arg702Trp (Hugot SNP8), Gly908Arg (Hugot SNP12), and Leu1007fsinsC (Hugot SNP13) and allele frequencies were compared between the Crohn's patients and controls. The correlation of NOD2/CARD15 genotypes with the phenotypic expression of Crohn's disease was further assessed by logistic regression analysis. RESULTS NOD2/CARD15 variants were found in 38/136 CD patients (27.9%) compared to 10/91 (10.9%) healthy controls (P = 0.0022). Allele frequencies in patients with CD were 13.97%, 4.4% and 11.76%, respectively, for SNP8, 12 and 13, compared to 5.49%, 1.12% and 4.40% in controls (P = 0.041, P = 0.162, P = 0.055). Six CD patients carried double mutations and, remarkably, we identified two homozygous mutants amongst the healthy control group. Surgery over the course of the disease and a younger age at onset of the disease were significantly more frequent in patients who were carriers of NOD2/CARD15 mutations. CONCLUSIONS This report on NOD2/CARD15 mutations in Croatian patients with CD demonstrates that this gene is also implicated in susceptibility to CD in the Croatian population. Phenotypic association showed a younger age at diagnosis and a higher need for surgery in patients carrying NOD2/CARD15 mutations. However, the prevalence is somewhat lower compared to other reports, likely due to a more prominent colonic inflammation.
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Affiliation(s)
- Silvija Cukovic-Cavka
- Division of Gastroenterology dDepartment of Pathology, University Hospital Rebro, Zagreb, Croatia.
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den Hartog JE, Ouburg S, Land JA, Lyons JM, Ito JI, Peña AS, Morré SA. Do host genetic traits in the bacterial sensing system play a role in the development of Chlamydia trachomatis-associated tubal pathology in subfertile women? BMC Infect Dis 2006; 6:122. [PMID: 16859562 PMCID: PMC1555588 DOI: 10.1186/1471-2334-6-122] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2006] [Accepted: 07/21/2006] [Indexed: 12/18/2022] Open
Abstract
Background In women, Chlamydia (C.) trachomatis upper genital tract infection can cause distal tubal damage and occlusion, increasing the risk of tubal factor subfertility and ectopic pregnancy. Variations, like single nucleotide polymorphisms (SNPs), in immunologically important host genes are assumed to play a role in the course and outcome of a C. trachomatis infection. We studied whether genetic traits (carrying multiple SNPs in different genes) in the bacterial sensing system are associated with an aberrant immune response and subsequently with tubal pathology following a C. trachomatis infection. The genes studied all encode for pattern recognition receptors (PRRs) involved in sensing bacterial components. Methods Of 227 subfertile women, serum was available for C. trachomatis IgG antibody testing and genotyping (common versus rare allele) of the PRR genes TLR9, TLR4, CD14 and CARD15/NOD2. In all women, a laparoscopy was performed to assess the grade of tubal pathology. Tubal pathology was defined as extensive peri-adnexal adhesions and/or distal occlusion of at least one tube. Results Following a C. trachomatis infection (i.e. C. trachomatis IgG positive), subfertile women carrying two or more SNPs in C. trachomatis PRR genes were at increased risk of tubal pathology compared to women carrying less than two SNPs (73% vs 33% risk). The differences were not statistically significant (P = 0.15), but a trend was observed. Conclusion Carrying multiple SNPs in C. trachomatis PRR genes tends to result in an aberrant immune response and a higher risk of tubal pathology following a C. trachomatis infection. Larger studies are needed to confirm our preliminary findings.
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Affiliation(s)
- Janneke E den Hartog
- Research Institute Growth and Development (GROW) and Department of Obstetrics and Gynaecology, Academic Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Sander Ouburg
- Laboratory of Immunogenetics, Section Immunogenetics of Infectious Diseases, Department of Pathology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
| | - Jolande A Land
- Research Institute Growth and Development (GROW) and Department of Obstetrics and Gynaecology, Academic Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
- On behalf of the ICTI consortium (Integrated approach to the study of Chlamydia trachomatis Infections) and the EpiGenChlamydia consortium
| | - Joseph M Lyons
- Department of Infectious Diseases, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, California 91010, USA
- On behalf of the ICTI consortium (Integrated approach to the study of Chlamydia trachomatis Infections) and the EpiGenChlamydia consortium
| | - James I Ito
- Department of Infectious Diseases, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, California 91010, USA
- On behalf of the ICTI consortium (Integrated approach to the study of Chlamydia trachomatis Infections) and the EpiGenChlamydia consortium
| | - A Salvador Peña
- Laboratory of Immunogenetics, Section Immunogenetics of Infectious Diseases, Department of Pathology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
- On behalf of the ICTI consortium (Integrated approach to the study of Chlamydia trachomatis Infections) and the EpiGenChlamydia consortium
| | - Servaas A Morré
- Laboratory of Immunogenetics, Section Immunogenetics of Infectious Diseases, Department of Pathology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
- Department of Internal Medicine, Section Infectious Diseases, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
- Department of Medical Microbiology, Academic Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
- On behalf of the ICTI consortium (Integrated approach to the study of Chlamydia trachomatis Infections) and the EpiGenChlamydia consortium
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Törkvist L, Noble CL, Lördal M, Sjöqvist U, Lindforss U, Nimmo ER, Russell RK, Löfberg R, Satsangi J. Contribution of CARD15 variants in determining susceptibility to Crohn's disease in Sweden. Scand J Gastroenterol 2006; 41:700-5. [PMID: 16716969 DOI: 10.1080/00365520500395245] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE 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. MATERIAL AND METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Leif Törkvist
- Department of Medical and Surgical Gastroenterology, Karolinska University Hospital, Stockholm, Sweden.
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Leong RWL, Lawrance IC, Chow DKL, To KF, Lau JY, Wu J, Leung WK, Chan FKL, Sung JJY. Association of intestinal granulomas with smoking, phenotype, and serology in Chinese patients with Crohn's disease. Am J Gastroenterol 2006; 101:1024-9. [PMID: 16573779 DOI: 10.1111/j.1572-0241.2006.00503.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Crohn's disease (CD) is a heterogenous disease characterized by variable manifestations and outcomes, and increasing in incidence in China. Phenotypic classification has been proposed to assist in subtyping of disease. Non-caseating intestinal granulomas are a hallmark of CD, but whether intestinal granulomas help predict Chinese CD phenotypes or determine severity, is not known. AIMS To determine the association between intestinal granulomas with CD phenotype, severity, risk factors, and serological markers. METHODS This was a single-centre study of consecutive definite Chinese CD cases. Granulomas were diagnosed by an experienced GI pathologist. Correlation with the Vienna Classification and other parameters was performed. RESULTS Eighty Chinese CD patients were recruited, 40 (50%) of whom had intestinal granulomas. Intestinal granulomas were independently associated with the stricturing behavior (OR: 4.71; 95% CI: 1.41-15.72), colonic location of disease (OR: 26.96; 95% CI: 2.68-271.14), but not with age of CD diagnosis. Current or previous smoking protected against the development of granulomas (OR: 0.16; 95% CI: 0.04-0.59). Granulomas were not associated with peri-anal involvement, extra-intestinal manifestations, anti-neutrophil cytoplasmic antibody or anti-Saccharomyces cerevisiae antibody serology, or severity of CD gauged by the requirement of major intestinal surgery or immunomodulating therapy. CONCLUSIONS Intestinal granulomas in the setting of CD may be helpful in determining phenotypic subtypes of CD, but is unhelpful in predicting disease severity. Smoking impairs the formation of granulomas in CD.
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Affiliation(s)
- Rupert W L Leong
- Faculty of Medicine, The University of New South Wales, Department of Gastroenterology, Bankstown-Lidcombe Hospital, Sydney, Australia
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Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12:1829-1841. [PMID: 16609988 PMCID: PMC4087507 DOI: 10.3748/wjg.v12.i12.1829] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 10/20/2005] [Accepted: 11/10/2005] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is only partially understood. Various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis (UC) or Crohn's disease (CD) or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors (e.g. NOD2/CARD15, SLC22A46A5 and DLG5). The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083 Budapest, Hungary.
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Casellas F, Vivancos JL, Sampedro M, Malagelada JR. Relevance of the phenotypic characteristics of Crohn's disease in patient perception of health-related quality of life. Am J Gastroenterol 2005; 100:2737-42. [PMID: 16393228 DOI: 10.1111/j.1572-0241.2005.00360.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Crohn's disease (CD) has a negative impact on patients' perception of health. Several factors, such as disease activity, influence HRQOL impairment. However, the effect of the phenotypic CD characteristics recognized in the Vienna classification on health-related quality of life (HRQoL) remains unknown. METHODS HRQOL was measured in CD patients using three questionnaires: the Spanish version of the Inflammatory Bowel Disease Questionnaire (IBDQ-36), the Psychological General Well-Being Index (PGWBI), and the EuroQol. RESULTS One hundred ninety-eight CD patients were included. Scores for the IBDQ-36, PGWBI, and EuroQol dimensions did not differ according to age at diagnosis (177 patients under 40 yr and 21 over 40 yr), disease location (53 in terminal ileum, 62 in colon, 72 in ileocolon, and 11 in upper gastrointestinal tract) or disease behavior (99 nonstricturing-nonpenetrating, 32 stricturing, and 67 penetrating). Multivariate analysis identified as significant independent variables for worse HRQoL: female sex (t: -3.70), higher number of relapses per year (t: -2.71), and worse clinical disease activity (t: -7.82). None of the three Vienna variables reached statistical significance. CONCLUSIONS HRQoL impairment in CD patients is independent of the clinical variables established in the Vienna classification for phenotypic type of disease.
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Affiliation(s)
- Francesc Casellas
- Unitat d'Atenció Crohn-Colitis, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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Russell RK, Drummond HE, Nimmo EE, Anderson N, Smith L, Wilson DC, Gillett PM, McGrogan P, Hassan K, Weaver LT, Bisset M, Mahdi G, Satsangi J. Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis 2005; 11:955-64. [PMID: 16239840 DOI: 10.1097/01.mib.0000183423.38037.f3] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. PATIENTS AND METHODS 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed. RESULTS The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]). CONCLUSIONS These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.
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Affiliation(s)
- Richard K Russell
- MRCPCH, Gastrointestinal Unit, Western General Hospital, Crewe Road, Edinburgh, Scotland.
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Karban A, Atia O, Leitersdorf E, Shahbari A, Sbeit W, Ackerman Z, Mualem R, Levine A, Nesher S, Safadi R, Eliakim R. The relation between NOD2/CARD15 mutations and the prevalence and phenotypic heterogeneity of Crohn's disease: lessons from the Israeli Arab Crohn's disease cohort. Dig Dis Sci 2005; 50:1692-7. [PMID: 16133971 DOI: 10.1007/s10620-005-2917-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2004] [Accepted: 01/05/2005] [Indexed: 12/17/2022]
Abstract
The prevalence of Crohn's disease depends on geographic location and racial background. Arg702Trp, Gly908Arg, and Leu1007fsinsC mutations in the NOD2/CARD15 gene are associated with Crohn's disease in Caucasians. The mutation rate among Israeli Jewish patients is 27%-41%. The prevalence of Crohn's disease is much lower in the Israeli Arab compared to the Israeli Jewish population. We studied the NOD2/CARD15 mutation rate and disease phenotype (according to the Vienna classification) among the Israeli Arabs and compared them with those in an Israeli Jewish cohort. We recruited 66 Israeli Arab patients and 122 ethnically matched controls. Five patients (8.2%) and three controls (2.3%) carried one NOD2/CARD15 mutation. The phenotypic characteristics of the Arab and Jewish patients were very similar. We conclude that NOD2/CARD15 mutations do not contribute to Crohn's susceptibility in the Israeli Arab population and suggest that NOD2/CARD15 mutations have an important effect on Crohn's prevalence within a specific population but not on the phenotype.
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Affiliation(s)
- Amir Karban
- Department of Gastroenterology, Rambam Medical Center, Haifa.
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Riis L, Munkholm P, Binder V, Skovgaard LT, Langholz E. Intra- and interobserver variation in the use of the Vienna classification of Crohn's disease. Inflamm Bowel Dis 2005; 11:657-61. [PMID: 15973120 DOI: 10.1097/01.mib.0000165115.18310.e7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Crohn's disease is a heterogeneous disease, and several classification systems have been developed to classify the patients in more homogeneous groups. Our aim was to assess the intra- and interobserver variation when classifying patients according to the widely used Vifenna classification. METHODS Ten randomly selected Crohn's disease cases were presented to 11 Danish gastroenterologists with a special interest in inflammatory bowel diseases. Clinical details, together with endoscopic, radiologic, and pathologic reports, were presented to the participants as a PowerPoint slide show, sent by e-mail with a data collection form. The experts were asked to classify the cases according to the Vienna classification and to evaluate intraobserver variation; the participants classified the patients 3 times. The strength of agreement was calculated using kappa statistics. RESULTS Classification of the patients according to age gave a kappa value of 1.00. The intraobserver kappa value was good, with an average kappa value of 0.75 (range, 0.42-0.86) for location and 0.77 (range, 0.53-1.00) for behavior. The mean overall interobserver kappa value was 0.64 (range, 0.12-1.00), which improved slightly between the first and third rounds. When classifying according to location and behavior, most patients were classified in 2 or 3 different ways, and in no patients was there full agreement among the observers for both location and behavior. CONCLUSIONS In this study, we found an overall good interobserver agreement when using the Vienna classification, although when looking at individual cases, there was some disagreement.
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Affiliation(s)
- Lene Riis
- Department of Medical Gastroenterology C, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
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Affiliation(s)
- Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
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Lakatos PL, Lakatos L, Szalay F, Willheim-Polli C, Osterreicher C, Tulassay Z, Molnar T, Reinisch W, Papp J, Mozsik G, Ferenci P. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. World J Gastroenterol 2005. [PMID: 15770725 DOI: 10.3748/wjg.v11.i10.1489.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
AIM To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP. RESULTS NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%, P<0.0001). SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (OR(het) = 1.71, 95%CI = 1.12-2.6, P = 0.0001, OR(two-risk alleles) = 25.2, 95%CI = 4.37-8, P<0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08, P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55, P = 0.026) and increased need for resection (OR=1.71, 95%CI: 1.13-2.62, P = 0.01), but not with duration, extra-intestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years. CONCLUSION These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083, Hungary.
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Lakatos PL, Lakatos L, Szalay F, Willheim-Polli C, Osterreicher C, Tulassay Z, Molnar T, Reinisch W, Papp J, Mozsik G, Ferenci P. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. World J Gastroenterol 2005; 11:1489-1495. [PMID: 15770725 PMCID: PMC4305691 DOI: 10.3748/wjg.v11.i10.1489] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2004] [Revised: 07/28/2004] [Accepted: 09/09/2004] [Indexed: 02/06/2023] Open
Abstract
AIM To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP. RESULTS NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%, P<0.0001). SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (OR(het) = 1.71, 95%CI = 1.12-2.6, P = 0.0001, OR(two-risk alleles) = 25.2, 95%CI = 4.37-8, P<0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08, P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55, P = 0.026) and increased need for resection (OR=1.71, 95%CI: 1.13-2.62, P = 0.01), but not with duration, extra-intestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years. CONCLUSION These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083, Hungary.
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Annese V, Lombardi G, Perri F, D'Incà R, Ardizzone S, Riegler G, Giaccari S, Vecchi M, Castiglione F, Gionchetti P, Cocchiara E, Vigneri S, Latiano A, Palmieri O, Andriulli A. Variants of CARD15 are associated with an aggressive clinical course of Crohn's disease--an IG-IBD study. Am J Gastroenterol 2005; 100:84-92. [PMID: 15654786 DOI: 10.1111/j.1572-0241.2005.40705.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Three major variants of the CARD15 gene confer susceptibility to Crohn's disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation. AIM We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives. METHODS Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unrelated healthy controls (HC) were studied. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated and correlated to age at diagnosis, gender, family history, localization, extraintestinal manifestations, previous resective surgery, stenosing/fistulizing pattern, ANCA, and ASCA. RESULTS Compared to HC, the frequencies of all three variants in CD were significantly increased: 8.7% versus 4.1% for R702W (p < 0.006), 7.3% versus 2.7% for G908R (p < 0.002), 9.3% versus 0.7% for L1007finsC (p < 0.00001). At least one risk allele was found in 38.2% (p < 0.0001, compared to HC), 13.7% (NS), and 15.1% of CD, UC, and HC, respectively. The L1007finsC risk allele was also significantly increased in unaffected relatives of familial (9.5%; p < 0.00001), and sporadic CD (9%; p < 0.00001), compared to HC (0.7%). Sixteen healthy relatives, carriers of two risk alleles, were asymptomatic after 5-8 yr of follow-up. CD carriers of at least one variant were younger (p= 0.03), more likely to have ileal localization (p= 0.0001), stenosing pattern (p= 0.01), previous resective surgery (p= 0.0001), and presence of ASCA (p= 0.0001). No difference in SNPs frequency between familial and sporadic cases of CD was found. CONCLUSION In our population, both familial and sporadic CD patients carrying at least one major variant of CARD15 had an aggressive clinical course.
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Affiliation(s)
- Vito Annese
- Gastroenterology Unit, CSS-IRCCS Hospital, Viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy
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Lu KC, Dietz DW. The Genetics of Inflammatory Bowel Disease. SEMINARS IN COLON AND RECTAL SURGERY 2004. [DOI: 10.1053/j.scrs.2005.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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