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Lipner EM, Greenberg DA. The Rise and Fall and Rise of Linkage Analysis as a Technique for Finding and Characterizing Inherited Influences on Disease Expression. Methods Mol Biol 2018; 1706:381-397. [PMID: 29423810 DOI: 10.1007/978-1-4939-7471-9_21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
For many years, family-based studies using linkage analysis represented the primary approach for identifying disease genes. This strategy is responsible for the identification of the greatest number of genes proven to cause human disease. However, technical advancements in next generation sequencing and high throughput genotyping, coupled with the apparent simplicity of association testing, led to the rejection of family-based studies and of linkage analysis. At present, genetic association methods, using case-control comparisons, have become the exclusive approach for detecting disease-related genes, particularly those underlying common, complex diseases. In this chapter, we present a historical overview of linkage analysis, including a description of how the approach works, as well as its strengths and weaknesses. We discuss how the transition from family-based studies to population comparison association studies led to a critical loss of information with respect to genetic etiology and inheritance, and we present historical and contemporary examples of linkage analysis "success stories" in identifying genes contributing to the development of human disease. Currently, linkage analysis is re-emerging as a useful approach for identifying disease genes, determining genetic parameters, and resolving genetic heterogeneity. We posit that the combination of linkage analysis, association testing, and high throughput sequencing provides a powerful approach for identifying disease-causing genes.
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Affiliation(s)
- Ettie M Lipner
- Center for Genes, Environment, and Health, National Jewish Health, 1400 Jackson Street, Denver, CO, 80602, USA.
- Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO, USA.
| | - David A Greenberg
- Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, Wexner Medical Center, Ohio State University, Columbus, OH, USA
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2
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Boukercha A, Mesbah-Amroun H, Bouzidi A, Saoula H, Nakkemouche M, Roy M, Hugot JP, Touil-Boukoffa C. NOD2/ CARD15 gene mutations in North Algerian patients with inflammatory bowel disease. World J Gastroenterol 2015; 21:7786-7794. [PMID: 26167078 PMCID: PMC4491965 DOI: 10.3748/wjg.v21.i25.7786] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/23/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria.
METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn’s disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher’s exact test where appropriate. Odds ratios (OR) and 95% confidence intervals (95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.
RESULTS: The p.Arg702Trp mutation showed the highest frequency in CD patients (8%) compared to UC patients (2%) (P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls (5%) (P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 3% vs 2% (P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1% (P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 1% vs 2% (P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1% (P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD (13%), than in HC (8%) and UC (5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.
CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.
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Cleynen I, Jüni P, Bekkering GE, Nüesch E, Mendes CT, Schmied S, Wyder S, Kellen E, Villiger PM, Rutgeerts P, Vermeire S, Lottaz D. Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review. PLoS One 2011; 6:e24106. [PMID: 21931648 PMCID: PMC3169567 DOI: 10.1371/journal.pone.0024106] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 08/04/2011] [Indexed: 12/11/2022] Open
Abstract
As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4 protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.
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Affiliation(s)
- Isabelle Cleynen
- Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium
| | - Peter Jüni
- Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | | | - Eveline Nüesch
- Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Camila T. Mendes
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
| | - Stefanie Schmied
- Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland
| | - Stefan Wyder
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
| | - Eliane Kellen
- Leuven Centre for Cancer Prevention, University Hospital Leuven, Leuven, Belgium
| | - Peter M. Villiger
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
| | - Paul Rutgeerts
- Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium
| | - Daniel Lottaz
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
- * E-mail:
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Anderson CA, Soranzo N, Zeggini E, Barrett JC. Synthetic associations are unlikely to account for many common disease genome-wide association signals. PLoS Biol 2011; 9:e1000580. [PMID: 21267062 PMCID: PMC3022527 DOI: 10.1371/journal.pbio.1000580] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Synthetic associations have been posited as a possible explanation for missing heritability in complex disease. We show several lines of evidence which suggest that, while possible, these synthetic associations are not common.
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Affiliation(s)
- Carl A Anderson
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB101HH, United Kingdom.
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5
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Feng Y, Zheng P, Zhao H, Wu K. SLC22A4 and SLC22A5 gene polymorphisms and Crohn's disease in the Chinese Han population. J Dig Dis 2009; 10:181-7. [PMID: 19659785 DOI: 10.1111/j.1751-2980.2009.00383.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Recent genomic surveys have identified two single nucleotide polymorphisms (SNP) in SLC22A4 and SLC22A5 as susceptibility loci for Crohn's disease (CD). We conducted the present study to assess whether the two SNP and exon variants in SLC22A4 and SLC22A5 could be implicated in the vulnerability to CD of the Chinese Han population. METHODS A total of 180 CD patients and 180 healthy controls were studied. Genotyping for the two positive sites and the SNP that we screened from all the exon regions in SLC22A4 and SLC22A5 were typed using the direct sequencing method. RESULTS Neither individual SNP nor any haplotype was found to be associated with CD in our case-control study. CONCLUSION In contrast to the Caucasian population, SLC22A4 and SLC22A5 genes are unlikely to play a major role in susceptibility to CD in the Chinese Han population.
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Affiliation(s)
- Yun Feng
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China
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Abstract
The concept that genetic variation underlies inter-individual differences in drug response and contributes to the risk of developing common, complex disorders is expanding rapidly. Consequently the interest in genetic translational research has increased. Polymorphic DNA markers, either microsatellites or single nucleotide polymorphisms (SNPs), are used to assess genetic identities and track genetic differences between individuals. Given their abundance and stability, SNPs hold great promise as markers for mapping disease susceptibility loci for common, complex disorders by association studies. For this purpose the development of inexpensive, accurate, high-throughput methods for scoring large numbers of SNPs from hundreds of patients and controls is critical. Furthermore, gene expression profiling using DNA microarrays is likely to become a useful diagnostic tool enabling classification of disease phenotype based on molecular basis of disease pathogenesis, revealing information that cannot be obtained by histological assessment. Moreover, identification of differentially expressed genes in affected versus control tissue or over time in affected tissue will lead to better understanding of the mechanisms underlying disease and ultimately to the development of more effective drug therapies. To illustrate the potential of genetic translational research, several examples in the field of gastroenterology are described.
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Affiliation(s)
- J J M Ter Linde
- Dept. of Gastroenterology, University Medical Centre Utrecht, The Netherlands.
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Underhill D, Braun J. Current understanding of fungal microflora in inflammatory bowel disease pathogenesis. Inflamm Bowel Dis 2008; 14:1147-53. [PMID: 18286647 PMCID: PMC3752988 DOI: 10.1002/ibd.20402] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel diseases are a current and growing public health problem, with a prevalence that appears to be increasing in most countries and cultures. While most research into the triggering phenomenon has focused on the interaction between commensal bacteria and inflammatory bowel disease, enteric fungi may also be important in determining disease susceptibility. Herein we review what is known about enteric fungi and the mechanisms by which they and their dysregulation might be involved in triggering inflammatory diseases of the bowel.
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Affiliation(s)
- David Underhill
- The Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California,The Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jonathan Braun
- The Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
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8
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Zaahl MG, Winter T, Warnich L, Kotze MJ. Analysis of the three common mutations in the CARD15 gene (R702W, G908R and 1007fs) in South African colored patients with inflammatory bowel disease. Mol Cell Probes 2006; 19:278-81. [PMID: 15967635 DOI: 10.1016/j.mcp.2005.03.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2003] [Revised: 12/21/2004] [Accepted: 03/30/2005] [Indexed: 02/02/2023]
Abstract
The caspase recruitment domain-containing protein 15 gene (CARD15) was recently identified as an important susceptibility gene for Crohn's disease (CD). The purpose of this study was to assess the likelihood that the three most common CARD15 mutations, R702W, G908R and 1007fs, contribute to inflammatory bowel disease (IBD) susceptibility in the South African colored population. The study cohort included 76 IBD patients, 41 with CD and 35 with ulcerative colitis (UC), and 100 population-matched controls. Mutations R702W, G908R and 1007fs were present at relatively low frequencies (<20%) in our study population. No statistically significant differences were furthermore, observed for these mutations between UC and CD patients or when compared with normal control individuals. Two additional mutations were identified, one novel (A661P) and one previously described (A725G), with the latter being identified in 4 of 35 (11%) UC patients. Statistically significant differences were obtained between UC and control individuals when comparing both allele (p<0.004, chi2 with Yates' correction=8.01) and genotype frequencies (p<0.004, chi2 with Yates' correction=8.14) for the A725G mutation, suggesting a possible role for this variant in disease expression.
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Affiliation(s)
- M G Zaahl
- Department of Genetics, University of Stellenbosch, Matieland, Stellenbosch 7602, South Africa.
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9
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Fidder H, Chowers Y, Ackerman Z, Pollak RD, Crusius JBA, Livneh A, Bar-Meir S, Avidan B, Shinhar Y. The familial Mediterranean fever (MEVF) gene as a modifier of Crohn's disease. Am J Gastroenterol 2005; 100:338-43. [PMID: 15667491 DOI: 10.1111/j.1572-0241.2005.40810.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Crohn's disease (CD) has been reported to be more frequent among non-Ashkenazi Jewish patients suffering from familial Mediterranean fever (FMF). Interestingly, functional similarities between the CD susceptibility gene (NOD2/CARD15) and the FMF gene (MEFV) have been described: both belong to the death domain containing protein family, important in the regulation of apoptosis, cytokine processing and inflammation. AIMS To investigate the prevalence of MEFV mutations in Jewish non-Ashkenazi CD patients and its putative effect on CD presentation. METHODS Germline DNA of 105 Israeli CD patients of non-Ashkenazi and mixed Ashkenazi-non-Ashkenazi ethnic background was analyzed for three most common MEFV mutations: M694V, V726A, and E148Q. Five patients (4.7%) with a clinical diagnosis of FMF were included. Data obtained from each patient included: age of onset, disease location, and behavior, the presence of extraintestinal manifestations of CD and therapeutic regimens. RESULTS The overall prevalence of mutation carriers among non-FMF-CD patients was 13% (13/100). A stricturing disease pattern was observed in 56% (10/18) of all carriers, FMF-CD, and non-FMF-CD patients, and in 25% (22/87) of noncarriers (OR: 3.7, 95% CI: 1.3-10.5, p= 0.015). The prevalence of fistulas was comparable in both groups. Extraintestinal manifestations were significantly more frequent among carriers than noncarriers (65%vs 32%, OR 3.9, 95% CI = 1.3-11.5, p= 0.015). No differences were observed in disease location and disease severity. CONCLUSIONS MEFV mutations are not associated with CD susceptibility, yet the presence of these mutations appears to be associated with a stricturing disease pattern and extraintestinal disease manifestations of CD.
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Affiliation(s)
- Herma Fidder
- Department of Gastroenterology and The Heller Institute of Medical Research, Chaim Sheba Medical Center, Tel Hashomer, Israel
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10
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Annese V, Piepoli A, Latiano A, Lombardi G, Napolitano G, Caruso N, Cocchiara E, Accadia L, Perri F, Andriulli A. HLA-DRB1 alleles may influence disease phenotype in patients with inflammatory bowel disease: a critical reappraisal with review of the literature. Dis Colon Rectum 2005; 48:57-65. [PMID: 15690658 DOI: 10.1007/s10350-004-0747-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The HLA region has been implicated in determining the disease susceptibility or the clinical phenotype of inflammatory bowel disease. The aim of this study was to assess the relation between HLA-DRB1 alleles with the clinical features of Crohn's disease and ulcerative colitis and the presence of anti-neutrophil cytoplasmic and anti-Saccharomyces cerevisiae antibodies. METHODS Blood samples were obtained from 102 Crohn's disease patients, 114 ulcerative colitis patients, and 264 unrelated healthy controls. Anti-neutrophil cytoplasmics were detected by a standard immunofluorescence method, and anti-Saccharomyces cerevisiaes were examined by an enzyme-linked immunosorbent assay immunoglobulin G/immunoglobulin A commercial assay. HLA-DRB1 typing of 26 alleles was performed by polymerase chain reaction sequence-specific primes. Patients were phenotyped according to gender, disease location, extent, and behavior, surgical resection, need of steroid, and anti-neutrophil cytoplasmic/anti-Saccharomyces cerevisiae status. RESULTS As a whole, after applying Bonferroni's correction for multiple comparisons, no significant association of HLA-DRB1 alleles with Crohn's disease or ulcerative colitis was found. After stratifying HLA-DRB1 alleles by clinical phenotypes of patients with ulcerative colitis, an excess of DRB1*1309*1320*1325*1329 allele (DR13) was found in conjunction with pancolitis (P < 0.0001), surgical resection (P < 0.0003), and extraintestinal manifestations (P < 0.0001). In Crohn's disease patients, an excess of DRB1*0304*0305*0307*0309 allele (DR3) was found in those with colonic disease (P < 0.0001) and patients with extraintestinal manifestations (P = 0.0003). This statistical association, however, emerged in only 3 of 114 patients with ulcerative colitis and in 3 of 102 patients with Crohn's disease. We found no association with the presence of anti-Saccharomyces cerevisiae or anti-neutrophil cytoplasmic. CONCLUSIONS Some clinical features of Crohn's disease and ulcerative colitis may be influenced by specific HLA-DR alleles; in particular, in ulcerative colitis some alleles appear to segregate with more aggressive disease, whereas in Crohn's disease different alleles cosegregate in patients with colonic disease and extraintestinal manifestations.
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Affiliation(s)
- V Annese
- Department of Internal Medicine, Unit of Gastroenterology and Endoscopy, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
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11
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Gazouli M, Zacharatos P, Mantzaris GJ, Barbatis C, Ikonomopoulos I, Archimandritis AJ, Lukas JC, Papalambros E, Gorgoulis V. Association of NOD2/CARD15 variants with Crohn's disease in a Greek population. Eur J Gastroenterol Hepatol 2004; 16:1177-1182. [PMID: 15489579 DOI: 10.1097/00042737-200411000-00016] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Single nucleotide polymorphisms in the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease (CD), but whether this susceptibility extends to all ethnic groups and geographic areas remains unknown. The aim of the present study was to evaluate the NOD2/CARD15 mutations in Greek patients with CD. METHODS Individuals were genotyped for three NOD2/CARD15 mutations: R702W, G908R and L1007fsinsC. Blood samples were obtained from 120 patients with CD, 85 patients with ulcerative colitis, and 100 unrelated healthy controls. RESULTS Mutations in NOD2/CARD15 were observed with significantly greater frequency in CD patients (98/120, 81.7%) than in ulcerative colitis patients (40/85, 47%) (P < 0.0001) or in healthy individuals (21/100, 21%) (P < 0.0001). For CD patients, compared with controls, the odds were increased for carriage of the R702W (odds ratio, 12.25) and less for the G908R (odds ratio, 5.2) and L1007fsinsC (odds ratio, 3.9) mutations. The age of onset of CD was lower in Greek mutation carriers as compared with non-carriers of Greek origin (28.2 +/- 14.6 years versus 34 +/- 12.3 years, respectively; P = 0.036). Additionally, the frequency of NOD2/CARD15 mutations was increased in ileitis or ileocolitis compared with non-ileal disease. CONCLUSIONS The NOD2/CARD15 mutations are risk factors for CD in Greece, they appear to predict an earlier age of onset and are associated particularly with ileitis or ileocolitis.
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Affiliation(s)
- Maria Gazouli
- Department of Histology-Embryology (Molecular Carcinogenesis Group), Medical School, University of Athens, Greece
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12
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Schreiber S, Hanpe J, Nikolaus S, Foelsch UR. Review article: exploration of the genetic aetiology of inflammatory bowel disease--implications for diagnosis and therapy. Aliment Pharmacol Ther 2004; 20 Suppl 4:1-8. [PMID: 15352887 DOI: 10.1111/j.1365-2036.2004.02058.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Genomic technologies offer new approaches to the investigation of the aetiology and pathophysiology of inflammatory bowel disease. An important field relevant to inflammatory bowel disease therapy is the pharmacogenetic investigation of gene variations that may predict responses to certain medications in order to target these therapeutic interventions more precisely. To date, only about 12,000 of the estimated 30,000-50,000 human genes have been characterized. Therefore, the use of techniques for a global analysis of gene expression may allow the identification of new pathways or molecules in the therapeutic mechanisms of drugs. Recently, NOD2 has been identified as the first disease gene in inflammatory bowel disease. DLGS and OCTN-1 have been named as further disease genes. Although the detection of disease-associated variants has greatly advanced our understanding of the primary events that lead to the development of inflammatory bowel disease in a subgroup of patients with Crohn's disease, the implications of the findings for diagnostic and therapeutic algorithms are less clear. However, it appears that there is a clear association between certain subphenotypes of Crohn's disease and the disease-associated variants in the NOD2 gene. It can be anticipated that genomic findings will profoundly influence the future therapy of inflammatory bowel disease.
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Affiliation(s)
- S Schreiber
- Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
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Ahmad T, Armuzzi A, Neville M, Bunce M, Ling KL, Welsh KI, Marshall SE, Jewell DP. The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis. ACTA ACUST UNITED AC 2004; 62:527-35. [PMID: 14617036 DOI: 10.1046/j.1399-0039.2003.00129.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Linkage and association studies implicate the human leucocyte antigen (HLA) region in genetic susceptibility to ulcerative colitis (UC). However, associations with specific variants have been inconsistent, even within defined ethnic groups. A genetic basis for the disease heterogeneity of UC may account for these discrepant findings from studies in unselected populations. Here, we examine the contribution of the HLA region to the clinical phenotype of UC. We studied 321 accurately phenotyped patients recruited from a single UK centre, with a median follow-up time of 15 years. Individuals were genotyped for 340 polymorphisms constructed into 25 gene-specific allelic haplotypes between HLA-A and Tapasin. Data were analysed with respect to age of onset, disease extent and severity. Strongest association with overall susceptibility was identified with HLA-DRB1 alleles replicating previous studies (DRB1*0103, DRB1*1502 and DRB1*0401). We report a novel association with homozygosity of a tumour necrosis factor (TNF) promoter haplotype (TNF-1031T, -863C, -857C, -380G, -308G and -238G) and distal disease extent that does not extend with time (distal vs total 40.9 vs 25.7%; RR = 2.0; 95% CI 1.23-3.24). We confirm the association of DRB1*0103 with total disease and/or disease requiring colectomy and further demonstrate that DRB1*0103 is associated with shorter time to surgery. Genes in the HLA play a role in modifying disease phenotype. Further studies are required to dissect how these genes functionally interact with each other and with environmental factors to determine clinical patterns of disease
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Affiliation(s)
- T Ahmad
- Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford, UK.
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Yap LM, Ahmad T, Jewell DP. The contribution of HLA genes to IBD susceptibility and phenotype. Best Pract Res Clin Gastroenterol 2004; 18:577-96. [PMID: 15157829 DOI: 10.1016/j.bpg.2004.01.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The human leukocyte antigen (HLA) region located on chromosome 6p encodes the highly polymorphic, classical class I and II genes essential for normal lymphocyte function; it also encodes a further 224 genes. Many early studies investigating this region were limited by small sample size, poor statistical methodology, population stratification and variable disease definition. Although more recent studies have improved study design, investigators are still challenged by the complex patterns of linkage disequilibrium across this gene-dense region, and by the disease heterogeneity characteristic of all genetically complex disorders. However, a number of important observations have emerged from recent studies: (1) the HLA harbours gene(s) that determine susceptibility to colonic inflammation in both ulcerative colitis (UC) and Crohn's disease (CD); (2) most of the specific associations with UC and CD appear to differ; (3) associations between different ethnic groups differ; (4) markers in the HLA might predict the course of disease and the development of complications, notably the extraintestinal manifestations of disease.
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Affiliation(s)
- Lee Min Yap
- Gastroenterology Unit, Gibson Laboratories, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK.
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Brant SR, Shugart YY. Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field. Inflamm Bowel Dis 2004; 10:300-11. [PMID: 15290927 DOI: 10.1097/00054725-200405000-00019] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Observed inflammatory bowel disease (IBD) familial clustering and increased monozygotic twin concordance has led to the hypothesis that genetic loci containing IBD susceptibility genes can be identified by whole genome linkage mapping approaches. Methodology including collecting carefully phenotyped multiplex pedigrees, genotyping using highly informative microsatellite markers and linkage analysis by non-parametric allele sharing methods has been established. Eleven published genome wide screens (GWS) have studied more than 1,200 multiplex IBD pedigrees. Two-thirds of affected relative pairs were Crohn's disease (CD), 20% ulcerative colitis (UC) and the remaining were mixed. Seven loci (IBDI-7) on chromosomes 16q, 12, 6p, 14q, 5q, 19, and 1p have been identified with genome wide significant and independently replicated linkage. Risk alleles/haplotypes have been defined for the IBD1 (CARD15/NOD2), IBD3 (HLA) and IBD5 (5q cytokine cluster) loci. There has been evidence for a second chromosome 16 locus (IBD8) independent of NOD2 that overlaps IBD1 on the pericentromeric p-arm. Several other regions show great promise for containing additional IBD loci, particularly chromosome 3p with genome wide evidence in one study at 3p26 and more centromeric evidence in several other studies, and chromosomes 2q, 3q, 4q, 7, 11p, and Xp each with suggestive evidence of linkage in one and additional evidence in two or more studies. Single GWSs and fine mapping studies containing very large sets of pedigrees and in particular, more UC pedigrees, and the use of creative analytic and disease stratification schemes are required to identify, establish and refine weaker IBD loci.
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Affiliation(s)
- Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine. Baltimore, Maryland, USA.
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Newman B, Silverberg MS, Gu X, Zhang Q, Lazaro A, Steinhart AH, Greenberg GR, Griffiths AM, McLeod RS, Cohen Z, Fernández-Viña M, Amos CI, Siminovitch K. CARD15 and HLA DRB1 alleles influence susceptibility and disease localization in Crohn's disease. Am J Gastroenterol 2004; 99:306-15. [PMID: 15046222 DOI: 10.1111/j.1572-0241.2004.04038.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Crohn's disease (CD) is a chronic inflammatory disease of the gut associated with allelic variants of CARD15 and HLA-DRB1 genes. We investigated the prevalence and effects of these variants in a Canadian CD cohort. METHODS 507 unrelated CD patients were genotyped for the three major CD-associated variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) and for thirteen HLA-DRB1 alleles. RESULTS At least one CARD15 variant was present in 32.5% of the CD patients compared with 20% of controls. The prevalence of CARD15 mutation was similar in both sporadic and familial and Jewish and non-Jewish CD patients. The Gly908Arg variant was significantly higher and the Arg702Trp variant significantly lower in Jewish compared to non-Jewish patients. A positive association between the HLA-DRB1*0103 allele and CD was detected in non-Jewish, familial cases (p = 0.0002), with risk for CD increased by 6.7 fold by the presence of an HLA-DRB1*0103 allele as compared to 1.9 fold and 19 fold by a single or two CARD15 variant alleles, respectively. We show a significant association of ileal involvement with CARD15 variants (OR = 1.8; p = 0.02), HLA-DRB1*0701 (OR = 1.9; p = 0.006) and DRB1*04 (OR = 1.7; p = 0.02) alleles and demonstrate the capacity of combined CARD15 and HLA-DRB1 genotyping to predict ileal disease in CD patients. By contrast, the HLA-DRB1*0103 allele was associated with later age of diagnosis (p = 0.02) and pure colonic disease (p = 0.000013). CONCLUSIONS These observations confirm the influence of CARD15 and HLA-DRB1 alleles on both CD susceptibility and site of disease and identify genotyping of these variants as a potential tool for improved diagnosis and risk prediction in CD.
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Affiliation(s)
- Bill Newman
- Department of Medicine, University of Toronto, Toronto, Canada
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17
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Andriulli A, Annese V, Latiano A, Palmieri O, Fortina P, Ardizzone S, Cottone M, D'Inca R, Riegler G. The frame-shift mutation of the NOD2/CARD15 gene is significantly increased in ulcerative colitis: an *IG-IBD study. Gastroenterology 2004; 126:625-627. [PMID: 14765396 DOI: 10.1053/j.gastro.2003.12.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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18
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Heresbach D, Gicquel-Douabin V, Birebent B, D'halluin PN, Heresbach-Le Berre N, Dreano S, Siproudhis L, Dabadie A, Gosselin M, Mosser J, Semana G, Bretagne JF, Yaouanq J. NOD2/CARD15 gene polymorphisms in Crohn's disease: a genotype- phenotype analysis. Eur J Gastroenterol Hepatol 2004; 16:55-62. [PMID: 15095853 DOI: 10.1097/00042737-200401000-00009] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Three recently identified NOD2/CARD15 mutations have been described associated with an increased susceptibility Crohn's disease (CD). Our aim was to examine the potential association of these NOD2 mutations with CD and different subsets of CD phenotypes in our population. METHODS Two hundred and five well-defined CD patients from north-western France and 95 ethnically matched healthy controls were genotyped for mutations R702W, G908R and Leu1007insC by DNA sequencing. Allele and genotype frequencies of NOD2 variants were examined in the whole series of CD and in different subgroups of CD phenotypes defined by the clinical characteristics of the Vienna classification (age at diagnosis, location and behaviour) or by histological features (granuloma). RESULTS Carriers of at least one NOD2/CARD15 variant were significantly more frequent in CD than in controls (38.0% versus 20.0%, P < 0.002), and the R702W allele was the most significant contributor to this NOD2 association with CD. Homozygotes and compound heterozygotes combined had a higher risk of CD (odds ratio = 12.0, P < 0.0026) than simple heterozygotes for any variant (odds ratio = 2.2, P < 0.013) compared with subjects with no variant. Univariate analysis revealed that carriage of at least one NOD2 mutation was significantly associated with ileal involvement (P < 0.03), and stricturing evolution (P < 0.0015). Granuloma was associated with an excess of the R702W allele (16.1% versus 8.0%, Pc < 0.035), and was correlated with a young age at diagnosis, whatever the NOD2/CARD15 genotype. Multivariate analysis demonstrated that carriage of NOD2/CARD15 mutants, especially R702W, was primarily and independently associated both with stricturing evolution of CD and the presence of granuloma. CONCLUSIONS In our population, all NOD2/CARD15 mutant genotypes, especially compound heterozygosity, were found to increase the risk of CD, but R702W was the sole allele showing a significant association with CD. In addition, we confirm the positive and independent association of the R702W mutation with stricturing behaviour and describe a second one with the presence of granuloma.
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Affiliation(s)
- Denis Heresbach
- Gastroenterology Department, CHU Pontchaillou and CEMDR, Rennes, France.
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Abstract
There is a general consensus that interplay of genetic and environmental factors leads to an overactive mucosal immune response, which mediates the tissue damage in inflammatory bowel disease. Ethnic aggregation of inflammatory bowel disease (particularly, increased incidence and prevalence in the Ashkenazim), familial aggregation of inflammatory bowel disease, and greater concordance for inflammatory bowel disease in monozygotic twins than dizygotic twins are 3 lines of evidence for a central role of genetic factors in the pathogenesis. The genetics of inflammatory bowel disease cannot be explained by simple Mendelian genetics; it is characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. Unraveling the complex genetics of inflammatory bowel disease is a daunting challenge, but the perseverance of inflammatory bowel disease gene hunters has produced commendable results in recent years. Since 1996, the field of inflammatory bowel disease genetics has progressed from publication of the first systematic genome searches for inflammatory bowel disease susceptibility loci to the identification of Crohn disease-associated genetic variants in CARD15/NOD2. Strategies for finding additional inflammatory bowel disease genes include taking advantage of the greater resolution and power of linkage disequilibrium mapping, mapping by admixture disequilibrium in African-American and Hispanic-American populations, stratifying genetic analyses by genotypes at known inflammatory bowel disease loci, and refining inflammatory bowel disease phenotypes to reduce genetic heterogeneity and simplify the search for additional inflammatory bowel disease genes.
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Affiliation(s)
- Richard H Duerr
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Palmieri O, Toth S, Ferraris A, Andriulli A, Latiano A, Annese V, Dallapiccola B, Vecchi M, Devoto M, Surrey S, Fortina P. CARD15 genotyping in inflammatory bowel disease patients by multiplex pyrosequencing. Clin Chem 2003; 49:1675-1679. [PMID: 14500598 DOI: 10.1373/49.10.1675] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Orazio Palmieri
- Department of Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19104, USA
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21
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Fidder HH, Olschwang S, Avidan B, Zouali H, Lang A, Bardan E, Picard O, Bar-Meir S, Colombel JF, Chowers Y. Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients. Am J Med Genet A 2003; 121A:240-4. [PMID: 12923865 DOI: 10.1002/ajmg.a.20209] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are heterogeneous disorders characterized by chronic intestinal inflammation. Genetic predisposition is a major risk factor in both diseases. The CARD15 (NOD2) gene has been implied as a candidate gene in the pathogenesis CD. Our aim was to delineate the frequency of three missense and one frameshift variant of CARD15 in Israeli Jewish CD and UC patients. DNA was extracted from blood samples from 238 unrelated inflammatory bowel disease (IBD) patients, 68 with UC and 170 with CD. The DNA was genotyped for two missense mutations, R675W and G881R, and one frameshift mutation, 980FS981X. Mutations in CARD15 were observed with significantly greater frequency in CD patients (46/170, 27%) than in UC patients (7/68, 10%) (P = 0.005). Homozygous and compound heterozygous carriers were restricted to seven (4%) patients with CD as compared to none of the UC patients (P = 0.01). Similar rates in Ashkenazi and non-Ashkenazi Jewish patients were observed. Age-of-onset of disease was lower in Ashkenazi mutation carriers as compared to non-carriers of Ashkenazi origin (18.7 +/- 8.6 years vs. 25.8 +/- 13.4 years, respectively, P = 0.03). No other phenotypic characteristics could distinguish mutation carriers from non-carriers. We conclude that germline mutations in the CARD15 gene are more frequently found in CD than UC patients and appear to predict an earlier age-of-onset in Ashkenazi Jewish patients. No association could be demonstrated between CARD15 mutations and specific disease course or behavior.
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Affiliation(s)
- Herma H Fidder
- Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel.
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22
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Zheng CQ, Hu GZ, Zeng ZS, Lin LJ, Gu GG. Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning. World J Gastroenterol 2003; 9:1646-56. [PMID: 12918095 PMCID: PMC4611518 DOI: 10.3748/wjg.v9.i8.1646] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes two clinical subtypes: Crohn disease (CD) and ulcerative colitis (UC). The general prevalence is about 1.0%-2.0% in Western countries. It is predominantly regarded as a multifactorial disorder involving environmental factors and polygenic defects. The view was confirmed by a lot of evidences from clinical attributions and animal models, especially from epidemiological investigations. So the etiological study of IBD has been focused on searching for susceptibility genes by positional cloning, which consists of two steps: linkage analysis and association analysis. Linkage analysis has been an important method of searching for susceptibility genes to polygenic diseases as well as single-gene disorders. IBD, as a polygenic disease, has been widely investigated by linkage analysis for susceptibility gene since 1996. The paper reviewed 38 articles, which covered almost all original researches in relation to IBD and linkage analysis. So far, several loci, such as 16q, 12q, 6p and 3p, have been identified by the studies. The most striking is 16q12 (IBD1), which linked only with CD not UC in the majority of studies. Association analysis, as one essential step for positional cloning, is usually carried out by genotyping candidate genes selected by means of linkage analysis or other methods, for figuring out the frequencies of alleles and comparing the frequencies between IBD group and healthy control group to identify the specific allele. It has been established that IBD is implicated in immune disorder. So the studies were centered on the genes of NOD2/CARD15, HLA-II, cytokine, cytokine receptor and adhesion molecule. This paper reviewed 14 original articles on association between NOD2 and IBD that have been published since 2001. All results, with the exception of one report from a Japanese group, provide evidences that the three kinds of variants of NOD2 are susceptibility factors for IBD. This article also comprehensively analyzed 18 original researches of HLA gene polymorphism in IBD. We found extensive discrepancy among the conclusions and a novel hypothesis was put forward to explain the discordance. Most studies published recently on association between IBD and cytokine gene polymorphism were reviewed.
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Affiliation(s)
- Chang-Qing Zheng
- Department of Gastroenterology, the Second Affiliated Clinical College of China Medical University, Shenyang 110001, Liaoning Province, China.
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23
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Peterson RL, Wang L, Albert L, Marchese E, Erickson J, Wong A, Mounts WM, Hayes L, Bouchard P, Keith J, Dorner AJ. Pharmacogenomic analysis of rhIL-11 treatment in the HLA-B27 rat model of inflammatory bowel disease. THE PHARMACOGENOMICS JOURNAL 2003; 2:383-99. [PMID: 12629504 DOI: 10.1038/sj.tpj.6500137] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2002] [Revised: 08/09/2002] [Accepted: 08/20/2002] [Indexed: 11/09/2022]
Abstract
Recombinant human interleukin-11 (rhIL-11) reduces the clinical signs and histological lesions of inflammatory bowel disease (IBD) in transgenic rats expressing the human major histocompatability complex (MHC) class I allele, HLA-B27. To elucidate the pharmacogenomic effects of rhIL-11 in this model, we examined the global gene expression pattern in inflamed colonic tissue before and following rhIL-11 treatment using oligonucleotide microarrays. In total, 175 disease-related genes were identified. Increased expression of genes involved in antigen presentation, cell death and inflammation, and decreased expression of metabolic genes was associated with disease. A total of 27 disease-related genes returned to normal expression levels following rhIL-11 treatment including the MHC class II gene RT1-DMbeta. rhIL-11 induced the expression of four intestinal epithelial growth factors. These gene expression patterns indicate that treatment of inflammatory bowel disease with rhIL-11 affects class II antigen processing and colonic epithelial cell proliferation and metabolism.
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Affiliation(s)
- R L Peterson
- Department of Molecular Medicine and Pharmacogenomics, 1 Burtt Road, Andover, MA, USA.
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24
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Ahmad T, Marshall S, Jewell D. Genotype-based phenotyping heralds a new taxonomy for inflammatory bowel disease. Curr Opin Gastroenterol 2003; 19:327-35. [PMID: 15703573 DOI: 10.1097/00001574-200307000-00002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) has traditionally been categorized as either ulcerative colitis or Crohn disease on the basis of clinical, radiologic, and histologic criteria. Within these diseases, however, significant heterogeneity is observed, suggesting the existence of phenotypic subtypes, based on features such as location and behavior of disease. Evidence for a possible genetic basis of these subgroups first emerged in the 1990s from epidemiologic studies in multiply affected families. Recent advances in our understanding of the genetics of IBD, in particular the identification of NOD2/CARD15, have provided the opportunity to explore the genetic basis for this heterogeneity. This article reviews recent studies investigating the contribution of genetics to IBD phenotype. Although many of the genes remain unidentified, the emerging data suggests that IBD comprises a heterogeneous family of oligogenic inflammatory disorders in which the specific clinical manifestations of disease in any individual are determined by the interaction of genetic and environmental factors. These data have validated the approach of classifying patients into accurately defined clinical subgroups, and they raise the possibility that a genetic basis for the observed disease heterogeneity may account for the discrepant findings from earlier genetic studies. A future molecular classification will provide the framework to understanding the different biologic mechanisms that underlie the clinical subgroups of IBD and, by patient stratification, permit the unraveling of the complex interaction between the genetic and environmental causes of disease.
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Affiliation(s)
- T Ahmad
- Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford, UK OX2 6QX.
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25
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Leong RWL, Armuzzi A, Ahmad T, Wong ML, Tse P, Jewell DP, Sung JJY. NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population. Aliment Pharmacol Ther 2003; 17:1465-70. [PMID: 12823148 DOI: 10.1046/j.1365-2036.2003.01607.x] [Citation(s) in RCA: 171] [Impact Index Per Article: 7.8] [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 affects people world-wide, but the incidence in Asia is lower than in Western countries. This difference may be due to genetic and/or environmental factors. Three single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene have been identified to be independently associated with the development of Crohn's disease in Caucasians. Whether these SNPs are involved in the pathogenesis of Crohn's disease in the Chinese population is unknown. AIM To determine if NOD2/CARD15 gene polymorphisms are found in Chinese patients with Crohn's disease. METHODS Sixty-five consecutive Chinese Crohn's disease patients had genotyping performed using sequence-specific PCR directed against the wild-type and the Arg702Trp, Gly908Arg and 3020insC variants of the NOD2/CARD15 gene. Controls consisted of 63 patients with ulcerative colitis and 70 patients with dyspepsia. RESULTS None of the patients with Crohn's disease had heterozygous or homozygous SNP variants. Similarly none of the ulcerative colitis or dyspeptic controls had these SNPs. CONCLUSION The three previously described SNPs associated with the development of Crohn's disease in Caucasians are not found in Chinese patients with Crohn's disease.
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Affiliation(s)
- R W L Leong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
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26
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Tamboli CP, Cortot A, Colombel JF. What are the major arguments in favour of the genetic susceptibility for inflammatory bowel disease? Eur J Gastroenterol Hepatol 2003; 15:587-92. [PMID: 12840667 DOI: 10.1097/00042737-200306000-00002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Epidemiological data, notably concordance rates in twin pairs and familial aggregation, have provided strong evidence for the importance of the genetic contribution in inflammatory bowel diseases. Genome wide scanning has been remarkably successful in identifying a number of susceptibility loci. The identification of the IBD1 gene on chromosome 16 as NOD2/CARD15 definitely establishes that a significant proportion of Crohn's disease has an underlying genetic cause. In addition, our knowledge of the clinical impact of other genes in modelling disease phenotypes has increased in parallel. These results have led to great optimism that important clinical applications will result from genetic research in the near future.
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Affiliation(s)
- Cyrus P Tamboli
- Department of Hepato-Gastroenterology, Hôpital Claude Huriez, Lille, France
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27
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Annese V, Latiano A, Andriulli A. Genetics of inflammatory bowel disease: the beginning of the end or the end of the beginning? Dig Liver Dis 2003; 35:442-449. [PMID: 12868683 DOI: 10.1016/s1590-8658(03)00213-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent identification of the first susceptibility gene for Crohn's disease has led to increasing enthusiasm for the investigation and dissection of inflammatory bowel disease. In the future, identification of additional genes and careful correlation of the genetic background with clinical features of the disease will help to elucidate the causes and cure of inflammatory bowel disease. However, caution is still needed in the short term since our present knowledge has limited influence on clinical management. This review focuses on the genetic background of inflammatory bowel disease, the process of discovering the mutations of the NOD2/CARD15 gene in Crohn's disease patients, and the functional clues of the genetic variants of this gene in relation to clinical features.
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Affiliation(s)
- V Annese
- Department of Internal Medicine, Gastroenterology Unit, "Casa Sollievo della Sofferenza" Hospital-I.R.C.C.S., 71013 San Giovanni Rotondo (Fg), Italy.
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28
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Linde KVD, Boor PPC, Houwing-Duistermaat JJ, Kuipers EJ, Wilson JHP, de Rooij FWM. Card15 and Crohn's disease: healthy homozygous carriers of the 3020insC frameshift mutation. Am J Gastroenterol 2003; 98:613-7. [PMID: 12650796 DOI: 10.1111/j.1572-0241.2003.07287.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Single nucleotide variations in the CARD15 gene have recently been shown to be associated with Crohn's disease (CD). Of special interest is a cytosine insertion at position 3020 of exon 11 (3020insC), which leads to a stop codon, truncation of the CARD15 protein, and an altered function of CARD15. The aim of the study was to evaluate this frameshift mutation in Dutch, multiple-affected families with inflammatory bowel disease (IBD). METHODS Ninety-three Caucasian, multiple-affected families with IBD were recruited by interviewing patients attending our department. Sixty-one probands had CD, and 32 probands ulcerative colitis (UC). The diagnosis of probands and affected family members was verified according to standard criteria. In addition, 81 healthy, unrelated controls were included. Genomic DNA was isolated from venous blood of all participants to determine the CARD15 3020insC mutation by using an allele-specific polymerase chain reaction, followed by agarose gel electrophoresis and DNA sequencing. RESULTS Association with CARD15 3020insC was statistically significant for CD, but not for UC. In one of the multiple-affected families, middle-aged and elderly homozygous carriers were identified without CD. CONCLUSIONS Although CARD15 3020insC appears to be etiologically important in CD, homozygous carriage does not always lead to IBD.
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Affiliation(s)
- Klaas van der Linde
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
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Xia B, Crusius JBA, Wu J, Zwiers A, van Bodegraven AA, Peña AS. Signal transducer and activator of transcription 6 gene G2964A polymorphism and inflammatory bowel disease. Clin Exp Immunol 2003; 131:446-50. [PMID: 12605697 PMCID: PMC1808642 DOI: 10.1046/j.1365-2249.2003.02079.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Signal transducer and activator of transcription 6 (STAT6) is a key transcription factor involved in interleukin 4 (IL-4) and IL-13-mediated Th2 response. The STAT6 gene is located on chromosome 12q13.3-14.1 (IBD2 region) and is therefore a positional and functional candidate gene for study in inflammatory bowel disease. We investigated the G2964A polymorphism in the 3' untranslated region of the STAT6 gene in Dutch patients with inflammatory bowel disease and healthy controls. The G2964A polymorphism in the STAT6 gene was genotyped in 141 unrelated Dutch Caucasian patients with ulcerative colitis, 183 patients with Crohn's disease and 173 healthy individuals by PCR and the amplification-created restriction site method. Patients with Crohn's disease were classified according to the Vienna classification and the patients with ulcerative colitis were classified with the age at onset, extent of disease and colectomy. We did not find significant differences in genotype and allele frequencies of the G2964A polymorphism in the STAT6 gene between ulcerative colitis, Crohn's disease and healthy controls. Subgroups of the patients with Crohn's disease classified according to the Vienna classification and those with ulcerative colitis classified according to age of onset, disease extension and colectomy did not differ in the distribution of this polymorphism. The STAT6 G2964A gene polymorphism is not involved in the overall susceptibility or in determining the phenotype of IBD.
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Affiliation(s)
- B Xia
- Department of Gastroenterology, Wuhan University Zhongnan Hospital, Wuhan, China.
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30
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Sugimura K, Taylor KD, Lin YC, Hang T, Wang D, Tang YM, Fischel-Ghodsian N, Targan SR, Rotter JI, Yang H. A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews. Am J Hum Genet 2003; 72:509-18. [PMID: 12577202 PMCID: PMC1180227 DOI: 10.1086/367848] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2002] [Accepted: 11/26/2002] [Indexed: 12/22/2022] Open
Abstract
Crohn disease (CD) exhibits a 2-4-fold increased frequency in Jews as compared with other ethnic/racial groups. Three coding variants of the NOD2/CARD15 have been reported as independent disease-predisposing mutations (DPMs), but these were found in only 30%-40% of patients with CD and could not account for all the linkage between CD and the IBD1 locus. The aim of the present study was to explore whether additional DPMs at the IBD1 locus exist in the high-risk Jewish group. Sixty-four Ashkenazi Jewish and 147 non-Jewish white families were studied. Six microsatellite markers spanning IBD1 were genotyped for linkage analysis in subgroups stratified on NOD2/CARD15 DPM status. SNPs in NOD2/CARD15 (R702W, G908R, 1007fs, and S268P) were then genotyped in family and independent case-control samples. On the basis of initial results, sequencing was done on NOD2/CARD15-translated regions in 12 Jewish individuals. Subsequently, a new NOD2/CARD15 variant was genotyped and analyzed. After excluding the influence of the three DPMs, significant linkage of IBD1 to CD in Jews remained with two peaks at D16S403 (mean allele sharing [MAS] = 0.70] and D16S411 (MAS = 0.59). Further, we observed an increased frequency of a haplotype carrying only the 268S variant in Jewish patients (OR = 3.13, P=.0023) but not in non-Jews, suggesting the existence of a Jewish-specific additional disease-predisposing factor on this haplotype. Sequencing of this haplotype revealed a new variant (IVS8+158; JW1). The 268S-JW1 combination exhibited a further increased risk (OR = 5.75, P=.0005) and the highest population-attributable risk (15.1%) for CD among reported DPMs in Jews. In Ashkenazi Jews, unrecognized population-specific predisposing factor(s) exist on the 268S-JW1 haplotype at the IBD1 locus. This factor may contribute to the higher risk for CD in Ashkenazi Jews as compared with non-Jews.
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Affiliation(s)
- Kazuhito Sugimura
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Kent D. Taylor
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Ying-chao Lin
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Tieu Hang
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Dai Wang
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Yong-Ming Tang
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Nathan Fischel-Ghodsian
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Stephan R. Targan
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Jerome I. Rotter
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
| | - Huiying Yang
- Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Departments of Medicine and Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and University of California at Los Angeles, Los Angeles
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Bonen DK, Ogura Y, Nicolae DL, Inohara N, Saab L, Tanabe T, Chen FF, Foster SJ, Duerr RH, Brant SR, Cho JH, Nuñez G. Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology 2003; 124:140-6. [PMID: 12512038 DOI: 10.1053/gast.2003.50019] [Citation(s) in RCA: 309] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The NOD2 variants R702W, G908R, and L1007fsinsC are strongly associated with Crohn's disease (CD) in both European and American populations, but whether this susceptibility extends to all ethnic groups remains unknown. Except for the L1007fsinsC mutation, which produces a truncated NOD2 protein, the functional activity of the major CD-associated variants G908R and R702W is unknown. METHODS Individuals were genotyped for R702W, G908R, and L1007fsinsC. The ability of G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S to confer responsiveness to lipopolysaccharide (LPS) and peptidoglycan (PGN) was determined in HEK293T kidney cells. RESULTS G908R and L1007fsinsC, but not R702W, were associated with disease susceptibility in Ashkenazi Jews. Ashkenazi Jews with CD had significantly higher allele frequency carriage of G908R and lower carriage of R702W compared with non-Jewish whites with CD. Functional studies revealed that the G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S are defective in their ability to respond to bacterial LPS and PGN, whereas P268S alone exhibited wild-type activity. CONCLUSIONS R702W is not associated with susceptibility to CD in Ashkenazi Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect in response to bacterial components, providing evidence for a unifying molecular mechanism whereby NOD2 mutations contribute to disease susceptibility.
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Affiliation(s)
- Denise K Bonen
- Martin Boyer Laboratories, Gastroenterology Section, Department of Medicine, University of Chicago Hospitals, Chicago, Illinois, USA
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Croucher PJP, Mascheretti S, Hampe J, Huse K, Frenzel H, Stoll M, Lu T, Nikolaus S, Yang SK, Krawczak M, Kim WH, Schreiber S. Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet 2003; 11:6-16. [PMID: 12529700 DOI: 10.1038/sj.ejhg.5200897] [Citation(s) in RCA: 185] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2002] [Revised: 08/22/2002] [Accepted: 08/26/2002] [Indexed: 01/13/2023] Open
Abstract
Current debate focuses on the relevance of linkage disequilibrium (LD), ethnicity and underlying haplotype structure to the search for genes involved in complex disorders. The recently described association between single nucleotide polymorphisms (SNPs) of the CARD15 (NOD2) gene and Crohn's disease (CD) in populations of north-European descent provides a test case that we have subjected to detailed SNP haplotype based analyses. We examined 23 SNPs spanning 290 kb, including CARD15, in large North-European and Korean samples of patients with Crohn's disease and normal controls. In Europeans we confirmed that the three disease-associated SNPs occur independently but share a common background haplotype. This suggests a common origin and the possibility of an undiscovered more strongly predisposing mutation. Korean CD patients present a phenotype identical to the European patients and have not previously been screened for CARD15. The three disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. Consequently, the disease-associated mutations in the Europeans, which are rare, have arisen recently (after the Asian-European split). Our results highlight important issues relevant to mapping the genes that predispose to complex disorders. First, although ethnically divergent populations may present identical phenotypes they do not necessarily share the same set of predisposing genes. Second, although single-locus tests of association showed consistent association with markers throughout the gene, pair-wise LD between markers (r(2) and D') yielded very little information about actual disease-association. Third, a population comparative approach allowed refining of the marker set through the examination of shared polymorphisms and common LD-groups. This approach, in conjunction with the examination of the mutational steps in a haplotype network, allows unambiguous identification of the potentially causative mutations.
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Affiliation(s)
- Peter J P Croucher
- 1st Department of Medicine, Christian-Albrechts-University, Kiel, Germany
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Cavanaugh JA, Adams KE, Quak EJ, Bryce ME, O'Callaghan NJ, Rodgers HJ, Magarry GR, Butler WJ, Eaden JA, Roberts-Thomson IC, Pavli P, Wilson SR, Callen DF. CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population. Ann Hum Genet 2003; 67:35-41. [PMID: 12556233 DOI: 10.1046/j.1469-1809.2003.00006.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.
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Affiliation(s)
- J A Cavanaugh
- The Canberra Hospital, Gilmore Crescent, Garran, ACT 2606.
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34
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Williams CN, Kocher K, Lander ES, Daly MJ, Rioux JD. Using a genome-wide scan and meta-analysis to identify a novel IBD locus and confirm previously identified IBD loci. Inflamm Bowel Dis 2002; 8:375-81. [PMID: 12454612 DOI: 10.1097/00054725-200211000-00001] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Seven loci that potentially confer susceptibility to inflammatory bowel disease (IBD) or one of its subtypes have been identified to date; however, most are unconfirmed, and the complete set of loci contributing to disease susceptibility has not yet been determined. The authors aim to identify loci contributing to disease susceptibility in an IBD population from Canada and to compare their results in a systematic manner with those of previously published IBD data sets. The authors performed genome-wide linkage analysis on 63 IBD families from Nova Scotia, Canada. They then undertook a meta-analysis to combine the results of their study with those of the four previously published IBD genome-wide scans with complete data reported. Their genome-wide scan identified three regions of suggestive linkage to IBD: 11p, and The locus on chromosome 11p has not been previously reported. Meta-analysis of multiple scans revealed linked regions corresponding to the, and loci. Meta-analysis of linkage data is a powerful approach for identifying and confirming common susceptibility loci and specifically shows that, and are the major, common IBD susceptibility loci in the populations studied thus far.
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Affiliation(s)
- C Noel Williams
- Queen Elizabeth II Health Sciences Center University Hospital, Nova Scotia, Canada
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35
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Abstract
Complex genetic disorders such as inflammatory bowel disease (IBD) result from the interplay between multiple genetic and environmental risk factors. The recent identification of variants of the CARD15/NOD2 protein as contributing to Crohn disease represents a major advance in defining disease pathogenesis. CARD15/NOD2 is expressed in monocytes and is capable of activating nuclear factor kappa B (NF-kappaB). Crohn disease-associated mutations in CARD15/NOD2 predominate in its C-terminus leucine-rich repeat domain, which is required for bacterial lipopolysaccharide-dependent induction of NF-kappaB activity. The relative risk of developing Crohn disease is estimated to be in the range of 2 to 3 in people carrying one mutation and 20 to 40 in people carrying two mutations in CARD15/NOD2. Homozygote and compound heterozygote carriers of CARD15/NOD2 mutations are characterized by an earlier age of onset, less involvement of the left colon, and positive association with stricturing disease. However, even carriers of two CARD15/NOD2 mutations have limited disease penetrance (ie, only a minority will develop the disease), suggesting that additional interacting genes and environmental triggers are required for disease expression. Several additional genetic regions have been implicated through genetic linkage and association studies.
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Abstract
The complex genetics of IBD is characterized by more than one susceptibility locus, genetic heterogeneity, incomplete penetrance, and probable gene-gene and gene-environment interactions. Functional candidate gene association studies during the past few decades have revealed only modest associations between IBD and genetic variants in the HLA genes and a limited number of other genes that are involved in immune regulation and the inflammatory response. Important advances in IBD genetics research have come about from systematic genome searches for IBD loci. The identification of Crohn's disease-associated NOD2 genetic variants that appear to alter the innate immune response to bacteria is a seminal finding that perhaps is the greatest advance toward understanding the pathogenesis of IBD in decades. The future discovery of other IBD genetic risk factors, facilitated by the completion of the human genome sequencing and annotation, may allow the development of better therapies, possibly including preventive therapies, for patients with Crohn's disease and ulcerative colitis.
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Affiliation(s)
- Richard H Duerr
- Inflammatory Bowel Disease Genetics Laboratory, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
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37
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Hampe J, Frenzel H, Mirza MM, Croucher PJP, Cuthbert A, Mascheretti S, Huse K, Platzer M, Bridger S, Meyer B, Nürnberg P, Stokkers P, Krawczak M, Mathew CG, Curran M, Schreiber S. Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc Natl Acad Sci U S A 2002; 99:321-6. [PMID: 11752413 PMCID: PMC117559 DOI: 10.1073/pnas.261567999] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2001] [Accepted: 10/24/2001] [Indexed: 02/07/2023] Open
Abstract
Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 "unknown." Significance at the central peak, corresponding to the genomic location of NOD2, then decreased from 3.2 to 1.2. The maximal lod scores on the proximal p-arm (lod = 2.1) and central q-arm (lod = 2.6) changed only moderately. An exploratory association analysis (TRANSMIT) yielded a strong lead at D16S3068 (P = 0.00028). The region around this marker was further investigated by using anonymous SNPs. An associated haplotype containing three SNPs was identified (peak significance P = 0.00027, IBD phenotype). On stratification based on NOD2 genotype, this significance increased to P = 0.0001. These results confirm the importance of NOD2 and provide evidence for a second IBD gene located on chromosome 16p.
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Affiliation(s)
- Jochen Hampe
- Department of General Internal Medicine, Christian Albrechts University, 24118 Kiel, Germany
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Gershon ES, Badner JA. Progress toward discovery of susceptibility genes for bipolar manic-depressive illness and schizophrenia. CNS Spectr 2001; 6:965-8, 977. [PMID: 15311192 DOI: 10.1017/s1092852900001073] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The inconsistency in linkage results that has bedeviled psychiatric genetics has been observed to occur regularly in common diseases with complex inheritance. Nonetheless, in two such instances--noninsulin-dependent diabetes mellitus (NIDDM) and inflammatory bowel disease (IBD)--susceptibility genes have been discovered based on the follow-ups of linkage findings. In bipolar illness disorder (BPD) and schizophrenia (SZ), there are some linkage reports with replication of other studies similar to the situation in NIDDM and IBD before the successful positional cloning efforts. Two of the regions with linkage reports, BPD and SZ, on the long arms of chromosomes 13 and 22, show linkage to the same markers in both diseases. This lends some plausibility to the hypothesis of some shared genetic predispositions for both disorders. Cytogenetic evidence offers another positional approach to susceptibility genes. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BPD and SZ. Endophenotypes of SZ, previously demonstrated to the be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to 6p, and an abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to the psychiatric illnesses. These genetic findings may contribute to etiologic subcategorization of BPD and SZ, and the development of new treatment approaches. A table of genetic terms is included for review
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Affiliation(s)
- E S Gershon
- Department of Psychiatry, University of Chicago, Chicago, Ill, USA.
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39
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Zouali H, Chamaillard M, Lesage S, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, Montague S, Gassull M, Christensen S, Finkel Y, Gower-Rousseau C, Modigliani R, Macry J, Selinger-Leneman H, Thomas G, Hugot JP. Genetic refinement and physical mapping of a chromosome 16q candidate region for inflammatory bowel disease. Eur J Hum Genet 2001; 9:731-42. [PMID: 11781683 DOI: 10.1038/sj.ejhg.5200710] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2001] [Revised: 06/29/2001] [Accepted: 07/03/2001] [Indexed: 01/03/2023] Open
Abstract
Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37x10(-4)) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P<0.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1.
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Affiliation(s)
- H Zouali
- Fondation Jean Dausset CEPH, Paris, France
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40
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Annese V, Andreoli A, Astegiano M, Campieri M, Caprilli R, Cucchiara S, D'Incà R, Giaccari S, Iaquinto G, Lombardi G, Napolitano G, Pera A, Riegler G, Valpiani D, Andriulli A. Clinical features in familial cases of Crohn's disease and ulcerative colitis in Italy: a GISC study. Italian Study Group for the Disease of Colon and Rectum. Am J Gastroenterol 2001; 96:2939-45. [PMID: 11693330 DOI: 10.1111/j.1572-0241.2001.04685.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (< 1 yr or > or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.
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Affiliation(s)
- V Annese
- Divisione di Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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Dechairo B, Dimon C, van Heel D, Mackay I, Edwards M, Scambler P, Jewell D, Cardon L, Lench N, Carey A. Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3). Eur J Hum Genet 2001; 9:627-33. [PMID: 11528509 DOI: 10.1038/sj.ejhg.5200687] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2001] [Revised: 05/09/2001] [Accepted: 05/16/2001] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine, commonly diagnosed as either ulcerative colitis (UC) or Crohn's disease (CD). Epidemiological studies have consistently shown that both genetic and environmental factors influence the pathogenesis of IBD. A number of genome scans have been conducted in cohorts of IBD families with affected sibling pairs (ASPs) to identify chromosomal regions that harbour IBD susceptibility genes. Several putative linked loci have been identified, including two loci on chromosomes 16 and 12, IBD1 and IBD2, which have subsequently been replicated by independent region-specific studies. We have conducted both a replication study on another linkage region, chromosome 6p (IBD3), and extension studies on two other regions, chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD ASPs from 234 families. A nonparametric peak multipoint LOD score of 3.0 was observed near D6S291, replicating the previous linkage to chromosome 6p (IBD3). Nominal evidence of linkage was observed at both the 3p and 7q regions.
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42
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Annese V, Andreoli A, Andriulli A, Dinca R, Gionchetti P, Latiano A, Lombardi G, Piepoli A, Poulain D, Sendid B, Colombel JF. Familial expression of anti-Saccharomyces cerevisiae Mannan antibodies in Crohn's disease and ulcerative colitis: a GISC study. Am J Gastroenterol 2001; 96:2407-12. [PMID: 11513182 DOI: 10.1111/j.1572-0241.2001.04043.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Recent studies in familial Crohn's disease (CD) have suggested that anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) may represent a new specific marker of genetic susceptibility. In this study we aimed to assess the importance of ASCAs by comparing their presence in a large number of patients with sporadic and familial occurrence of CD or ulcerative colitis (UC) and their unaffected relatives. METHODS Serum samples from 96 patients with sporadic CD, 97 patients with sporadic UC, and 50 unrelated healthy controls were tested for ASCAs by a standard ELISA method. Moreover, 73 families with two or more members affected by CD and/or UC were recruited. From these families 58 CD patients, 84 UC patients, and 216 unaffected first degree relatives were investigated. RESULTS ASCAs were detected in 34 of 96 patients with sporadic CD (35%, p < 0.01 vs controls), 11 of 97 patients with sporadic UC (12%), and two of 50 controls (4%). ASCAs were significantly (p < 0.04) more frequent in patients with familial CD (55%) and familial UC (25%) than in sporadic cases. Moreover, ASCAs were found in 25% of unaffected relatives, and this rate did not significantly differ in CD, UC, and mixed families (28%, 26%, and 22%, respectively). CONCLUSIONS In this study we confirm that ASCAs occur particularly frequently in CD patients, especially with the presence of a positive family history. However, they are also significantly increased in UC patients with a family history and in a considerable number of unaffected relatives of inflammatory bowel disease families, irrespective of the characteristics of their families (UC, CD, mixed, ASCA positive, and ASCA negative). The presence of ASCAs in unaffected relatives might point toward a genetic predisposition to either CD or UC.
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Affiliation(s)
- V Annese
- Divisione di Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 2001; 357:1925-8. [PMID: 11425413 DOI: 10.1016/s0140-6736(00)05063-7] [Citation(s) in RCA: 764] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent populations. The recently identified NOD2 gene is a good positional and functional candidate gene since it is located in the region of linkage on chromosome 16q12, and activates nuclear factor (NF) kappaB in response to bacterial lipopolysaccharides. Methods We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls. We then tested for association with Crohn's disease and ulcerative colitis. Findings Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combined p<0.0001); the association was confirmed in the 304 German trios with Crohn's disease. No association was seen in the 115 sibling pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 (95% CI 1.5-4.5) and 42.1 (4.3-infinity), respectively. Interpretation The insertion mutation in the NOD2 gene confers a substantially increased susceptibility to Crohn's disease but not to ulcerative colitis.
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Affiliation(s)
- J Hampe
- Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
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Abstract
Epidemiological data, particularly concordance rates in twin pairs and in multiply affected families, provide strong evidence that both genetic and environmental influences are important in the development of the chronic intestinal inflammation characteristic of Crohn disease and ulcerative colitis. Furthermore, supplementary data now suggest that not only susceptibility, but also disease behavior and response to therapy may have a strong genetic influence. The model of disease susceptibility most pertinent to the inflammatory bowel diseases is that Crohn disease and ulcerative colitis are related polygenic disorders. Recently, this model has received strong support from the results of genome-wide scanning and candidate gene studies carried out in European, North American and Australian populations. In spite of all potential difficulties related to disease and ethnic heterogeneity, consistent replication of linkage has been found with distinct regions on chromosomes 16, 12, 6 (the major histocompatibility complex) and most recently chromosome 14. Whereas the linkages on chromosome 16 and 14 appear strongest in Crohn disease, the chromosome 12 locus appears most pertinent to ulcerative colitis, and the HLA region appears more pertinent in all forms of inflammatory bowel disease. The current challenge is to narrow these regions of linkage and identify the susceptibility genes within the regions. The task may be greatly benefited by the recent successful sequence data available from the human genome project. Compelling data have emerged to suggest genetic markers that may allow prediction of disease severity, and efficacy and tolerability of immuno-suppressants commonly used in inflammatory bowel disease.
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MESH Headings
- Chromosomes, Human, Pair 12/genetics
- Chromosomes, Human, Pair 14/genetics
- Chromosomes, Human, Pair 16/genetics
- Chromosomes, Human, Pair 6/genetics
- Colitis, Ulcerative/etiology
- Colitis, Ulcerative/genetics
- Crohn Disease/etiology
- Crohn Disease/genetics
- Disease Susceptibility
- Environment
- Genetic Linkage
- Genetic Markers/genetics
- Genome, Human
- HLA Antigens/genetics
- Humans
- Inflammatory Bowel Diseases/etiology
- Inflammatory Bowel Diseases/genetics
- Major Histocompatibility Complex/genetics
- Models, Genetic
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Affiliation(s)
- J Satsangi
- Western General Hospital, University of Edinburgh, UK.
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45
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Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP. Review article: the genetics of inflammatory bowel disease. Aliment Pharmacol Ther 2001; 15:731-48. [PMID: 11380312 DOI: 10.1046/j.1365-2036.2001.00981.x] [Citation(s) in RCA: 115] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn's disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome-wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3-the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the 'positional' candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications.
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Affiliation(s)
- T Ahmad
- Gastroenterology Unit, Radcliffe Infirmary, Oxford, UK.
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46
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Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411:603-6. [PMID: 11385577 DOI: 10.1038/35079114] [Citation(s) in RCA: 3463] [Impact Index Per Article: 144.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.
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Affiliation(s)
- Y Ogura
- Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
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47
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Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet 2001; 68:1165-1171. [PMID: 11309682 PMCID: PMC1226097 DOI: 10.1086/320119] [Citation(s) in RCA: 149] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2001] [Accepted: 03/08/2001] [Indexed: 11/03/2022] Open
Abstract
Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high-penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits.
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Affiliation(s)
- J Cavanaugh
- Gastroenterology Research Unit, The Canberra Hospital, Woden, ACT, Australia.
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48
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Parkes M, Barmada MM, Satsangi J, Weeks DE, Jewell DP, Duerr RH. The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. Am J Hum Genet 2000; 67:1605-10. [PMID: 11078482 PMCID: PMC1287939 DOI: 10.1086/316905] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2000] [Accepted: 10/10/2000] [Indexed: 01/03/2023] Open
Abstract
The IBD2 locus on chromosome 12 has been linked to both Crohn disease (CD) and ulcerative colitis (UC) but has not been detected in some CD-dominated data sets. In the present study, we genotyped 581 relative pairs with inflammatory bowel disease (252 from CD-only families, 138 from UC-only families, and 191 from mixed families containing cases of both CD and UC), using 12 markers spanning the IBD2 locus. A GENEHUNTER-PLUS multipoint LOD score of 3.91 was detected for pairs from UC-only families, compared with 1.66 for CD-only and 1.29 for mixed families. The difference between the LOD scores for UC and CD was significant in two different tests for heterogeneity (P=.0057 for one test and P=.0375 for the other). IBD2 thus appears to make a major contribution to UC susceptibility but to have only a relatively minor effect with regard to CD, for which there may be substantially more locus heterogeneity.
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Affiliation(s)
- Miles Parkes
- Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary, and The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Department of Human Genetics, Graduate School of Public Health, and Department of Medicine and Center for Genomic Sciences, School of Medicine, University of Pittsburgh, Pittsburgh
| | - M. Michael Barmada
- Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary, and The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Department of Human Genetics, Graduate School of Public Health, and Department of Medicine and Center for Genomic Sciences, School of Medicine, University of Pittsburgh, Pittsburgh
| | - Jack Satsangi
- Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary, and The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Department of Human Genetics, Graduate School of Public Health, and Department of Medicine and Center for Genomic Sciences, School of Medicine, University of Pittsburgh, Pittsburgh
| | - Daniel E. Weeks
- Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary, and The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Department of Human Genetics, Graduate School of Public Health, and Department of Medicine and Center for Genomic Sciences, School of Medicine, University of Pittsburgh, Pittsburgh
| | - Derek P. Jewell
- Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary, and The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Department of Human Genetics, Graduate School of Public Health, and Department of Medicine and Center for Genomic Sciences, School of Medicine, University of Pittsburgh, Pittsburgh
| | - Richard H. Duerr
- Gastroenterology Unit, Nuffield Department of Medicine, Radcliffe Infirmary, and The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Department of Human Genetics, Graduate School of Public Health, and Department of Medicine and Center for Genomic Sciences, School of Medicine, University of Pittsburgh, Pittsburgh
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49
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Pera A, Sostegni R, Daperno M, Ercole E, Laudi C, Rocca R, Rigazio C, Astegiano M, Rocca G. Genotype-phenotype relationship in inflammatory bowel disease. Eur J Intern Med 2000; 11:204-209. [PMID: 10967508 DOI: 10.1016/s0953-6205(00)00092-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases of unknown etiology. Much effort has been made in the last years to clarify the pathogenesis of inflammatory bowel disease (IBD). Data are not conclusive at the moment, but the most important known risk factor for developing IBD is a positive familial history. Genetic analyses have shown a linkage between loci on several chromosomes and IBD (IBD1 gene on chromosome 16 for CD and on chromosome 12 for UC). The association of genotype to specific phenotypes of disease could be hypothesized by the concordance of clinical characteristics in familial IBD, by the association of specific HLA haplotypes to clinically different groups of patients, and by different responses to treatment related to different polymorphisms of other chromosome 6 genes. The clinical heterogeneity of IBD has led to classifications of patients with Crohn's disease based upon clinical features (e.g. Rome and Vienna classifications) that allow the identification of subgroups of patients with similar clinical behavior. The possible drawbacks of these classifications are the lack of validation of intra-interobserver concordance, the absence of prospective evaluations, and stratification into too many subgroups. Furthermore, in our experience, clinical presentation (surgical or medical) seems to have a good correlation with prognosis, is easy identifiable, and can be applied at the time of diagnosis. In UC, extension of disease and clinical behavior correlate with prognosis. For these reasons, studies correlating genotype to phenotype should be performed to improve our knowledge of the diseases and possibly to stratify patients into different subgroups for more personalized treatments, in clinical trials and for research purposes.
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Affiliation(s)
- A Pera
- Gastroenterology Department, Ospedale Mauriziano Umberto I, Turin, Italy
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50
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Abstract
Genomic technologies offer new approaches to the investigation of etiology and pathophysiology of inflammatory bowel disease (IBD). Several areas of application for these new technologies are possible. One such application is the search for gene variations predisposing to the development of the disorder in multiply-affected families. Genome-wide linkage studies have defined replicated susceptibility regions for IBD on chromosomes 6, 12, and 16. These susceptibility regions are still very large and each contain several hundred positional candidate genes. Efforts are under way at several centers to define the underlying molecular variants using systematic linkage disequilibrium and candidate gene methods. The pharmacogenetic investigation of gene variations may predict response to certain medications to target these therapeutic interventions more precisely. The use of global gene expression technologies may allow the identification of new pathways or molecules in the inflammatory process. This seems to be especially relevant because currently only approximately 8,000 of the estimated 100,000 human genes are characterized. In summary, genomic methodologies will profoundly influence the progress of IBD research and may lead to novel insights into both etiology and pathophysiology of chronic intestinal inflammation.
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Affiliation(s)
- S Schreiber
- Ist Department of Medicine, Christian-Albrechts-University, Kiel, Germany.
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