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El Hadad J, Schreiner P, Vavricka SR, Greuter T. The Genetics of Inflammatory Bowel Disease. Mol Diagn Ther 2024; 28:27-35. [PMID: 37847439 PMCID: PMC10787003 DOI: 10.1007/s40291-023-00678-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2023] [Indexed: 10/18/2023]
Abstract
The genetic background of inflammatory bowel disease, both Crohn's disease and ulcerative colitis, has been known for more than 2 decades. In the last 20 years, genome-wide association studies have dramatically increased our knowledge on the genetics of inflammatory bowel disease with more than 200 risk genes having been identified. Paralleling this increasing knowledge, the armamentarium of inflammatory bowel disease medications has been growing constantly. With more available therapeutic options, treatment decisions become more complex, with still many patients experiencing a debilitating disease course and a loss of response to treatment over time. With a better understanding of the disease, more effective personalized treatment strategies are looming on the horizon. Genotyping has long been considered a strategy for treatment decisions, such as the detection of thiopurine S-methyltransferase and nudix hydrolase 15 polymorphisms before the initiation of azathioprine. However, although many risk genes have been identified in inflammatory bowel disease, a substantial impact of genetic risk assessment on therapeutic strategies and disease outcome is still missing. In this review, we discuss the genetic background of inflammatory bowel disease, with a particular focus on the latest advances in the field and their potential impact on management decisions.
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Affiliation(s)
- Jasmina El Hadad
- Department of Internal Medicine, Triemli Hospital, Zurich, Switzerland
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Schreiner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Center for Gastroenterology and Hepatology, Zurich, Switzerland
| | - Thomas Greuter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
- Division of Gastroenterology and Hepatology, University Hospital Lausanne-CHUV, Lausanne, Switzerland.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, GZO Zurich Regional Health Center, Spitalstrasse 66, 8620, Wetzikon, Switzerland.
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Wang MH, Friton JJ, Rebert N, Monroe K, Nix BD, Fiocchi C, Raffals LE, Leighton JA, Pasha SF, Picco MF, Newberry RD, Achkar JP, Faubion WA. Novel Genetic Risk Variants and Clinical Predictors Associated With Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis. Clin Transl Gastroenterol 2023; 14:e00615. [PMID: 37440754 PMCID: PMC10522100 DOI: 10.14309/ctg.0000000000000615] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.
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Affiliation(s)
- Ming-Hsi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Gastroenterology, Mayo Clinic Health System, Southwest Minnesota Region, Mankato, Minnesota, USA
| | - Jessica J. Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nancy Rebert
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kelly Monroe
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Billy D. Nix
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jonathan A. Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Shabana F. Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Michael F. Picco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Rodney D. Newberry
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Jean-Paul Achkar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | - William A. Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
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3
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Degenhardt F, Mayr G, Wendorff M, Boucher G, Ellinghaus E, Ellinghaus D, ElAbd H, Rosati E, Hübenthal M, Juzenas S, Abedian S, Vahedi H, Thelma BK, Yang SK, Ye BD, Cheon JH, Datta LW, Daryani NE, Ellul P, Esaki M, Fuyuno Y, McGovern DPB, Haritunians T, Hong M, Juyal G, Jung ES, Kubo M, Kugathasan S, Lenz TL, Leslie S, Malekzadeh R, Midha V, Motyer A, Ng SC, Okou DT, Raychaudhuri S, Schembri J, Schreiber S, Song K, Sood A, Takahashi A, Torres EA, Umeno J, Alizadeh BZ, Weersma RK, Wong SH, Yamazaki K, Karlsen TH, Rioux JD, Brant SR, Franke A. Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations. Hum Mol Genet 2021; 30:356-369. [PMID: 33555323 PMCID: PMC8098114 DOI: 10.1093/hmg/ddab017] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/27/2020] [Accepted: 12/23/2020] [Indexed: 12/24/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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Affiliation(s)
- Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Gabriele Mayr
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Mareike Wendorff
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Gabrielle Boucher
- Research Center, Montréal Heart Institute, Université de Montréal and the Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada
| | - Eva Ellinghaus
- K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
| | - Hesham ElAbd
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Elisa Rosati
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Matthias Hübenthal
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Department of Dermatology, Venerology and Allergy, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Simonas Juzenas
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Shifteh Abedian
- Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, The Netherlands.,Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
| | - Homayon Vahedi
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
| | - B K Thelma
- Department of Genetics, University of Delhi South Campus, New Delhi, Delhi 110021, India
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Lisa Wu Datta
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Naser Ebrahim Daryani
- Department of Gastroenterology, Emam Hospital, Tehran University of Medical Sciences, Tehran 1419733141, Iran
| | - Pierre Ellul
- Department of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Motohiro Esaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yuta Fuyuno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama 351-0198, Japan
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Myhunghee Hong
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 136-701 Korea
| | - Garima Juyal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, Delhi 110067, India
| | - Eun Suk Jung
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, 351-0198, Japan
| | - Subra Kugathasan
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.,Pediatric Institute, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Tobias L Lenz
- Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany
| | - Stephen Leslie
- Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia
| | - Reza Malekzadeh
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
| | - Vandana Midha
- Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India
| | - Allan Motyer
- Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong
| | - David T Okou
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.,Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.,Centre for Genetics and Genomics Versus Arthritis, Division of Musculosceletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK
| | - John Schembri
- Department of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Department of Medicine, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 136-701 Korea
| | - Ajit Sood
- Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India
| | - Atsushi Takahashi
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, Riken, Yokohama, 230-0045, Japan
| | - Esther A Torres
- Department of Medicine, University of Puerto Rico Center for IBD, University of Puerto Rico School of Medicine, Rio Piedras, San Juan, PR 00936-5067, USA
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700 AB Groningen, The Netherlands
| | - Sunny H Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong
| | - Keiko Yamazaki
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama 351-0198, Japan
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway.,Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, 0372 Oslo, Norway
| | - John D Rioux
- Research Center, Montréal Heart Institute, Université de Montréal and the Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada
| | - Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Medicine, Rutgers Robert Wood Johnson School of Medicine and Department of Genetics, Rutgers University Brunswick and Piscataway, NJ 08903-0019, USA
| | | | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
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Wu X, Liang TY, Wang Z, Chen G. The role of hyperbaric oxygen therapy in inflammatory bowel disease: a narrative review. Med Gas Res 2021; 11:66-71. [PMID: 33818446 PMCID: PMC8130665 DOI: 10.4103/2045-9912.311497] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease is a group of chronic recurrent diseases in the digestive tract, including ulcerative colitis and Crohn's disease. Over the past few decades, the treatment of IBD has made great progress but there is still a lot of room for improvement. Hyperbaric oxygen therapy (HBOT) was defined as the therapeutic effect of inhaling 100% oxygen higher than one atmosphere and reported to be used in stroke, decompression sickness and wound healing. Since several authors reported the role of HBOT as an adjunct to conventional medical treatment in patients with refractory IBD, the relevant research has shown an increasing trend in recent years. Clinical and experimental studies have revealed that HBOT may exert its therapeutic effect by inhibiting inflammation and strengthening the antioxidant system, promoting the differentiation of colonic stem cells and recruiting cells involved in repair. The purpose of this review is to summarize the past clinical and experimental studies and to understand the impact of HBOT in the treatment of IBD more deeply. In addition, we also hope to provide some ideas for future clinical and research work.
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Affiliation(s)
- Xin Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Tian-Yu Liang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Bengi G, Cıvak M, Akarsu M, Soytürk M, Ellidokuz E, Topalak Ö, Akpınar H. Prevalance of Celiac Disease in Patients with Inflammatory Bowel Disease in Turkish Population. Gastroenterol Res Pract 2019; 2019:6272098. [PMID: 31885543 PMCID: PMC6927052 DOI: 10.1155/2019/6272098] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/04/2019] [Accepted: 11/26/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Celiac disease (CD) and inflammatory bowel disease (IBD) involve inflammation of the gastrointestinal lumen, which environmental, genetic, and immunological factors have a role in their pathogenesis. The prevalence of celiac disease in IBD ranges from 0% to 14%. In this study, our aim was to determine the prevalence of CD in IBD patients followed by us who are attending the hospital or outpatient clinic over a period of time of seven years. METHODS Seven hundred and fifty nine patients (425 M, 334 F, mean age: 46.75, 396 ulcerative colitis (UC), 363 Crohn's disease (CrD)) diagnosed and followed up for IBD between January 2009 and July 2016 were evaluated retrospectively, and clinical, demographic, laboratory, and endoscopic data were collected. RESULTS CD was investigated in 79 (%10.4) inflammatory bowel disease patients according to symptoms, and in 5.06% (n = 4) of them, we diagnosed CD. The most common indication for investigating for CD was iron deficiency anemia unreponsive to iron supplementation. CONCLUSIONS We did not find an increased prevalance of celiac disease in Turkish IBD patients in this study. In the presence of refractory iron deficiency anemia without any other cause in IBD patients, investigations for celiac disease should be considered.
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Affiliation(s)
- Göksel Bengi
- Gastroenterology Unit, Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Musa Cıvak
- Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Mesut Akarsu
- Gastroenterology Unit, Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Müjde Soytürk
- Gastroenterology Unit, Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Ender Ellidokuz
- Gastroenterology Unit, Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Ömer Topalak
- Gastroenterology Unit, Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Hale Akpınar
- Gastroenterology Unit, Department of Internal Medicine, Dokuz Eylül University, İzmir, Turkey
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Salehi Z, Gholaminia Z, Gholaminia M, Panjtanpanah M. Heat shock protein polymorphisms provide age-related cataract susceptibility for the population of Northern Iran. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Salehi Z, Gholaminia M, Gholaminia Z, Panjtanpanah M, Qazvini MG. The GG genotype of the HSPA1B gene is associated with increased risk of glaucoma in northern Iran. Mol Biol 2017. [DOI: 10.1134/s0026893316060182] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Assessing DNA methylation in the developing human intestinal epithelium: potential link to inflammatory bowel disease. Mucosal Immunol 2016; 9:647-58. [PMID: 26376367 PMCID: PMC4854977 DOI: 10.1038/mi.2015.88] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/27/2015] [Indexed: 02/04/2023]
Abstract
DNA methylation is one of the major epigenetic mechanisms implicated in regulating cellular development and cell-type-specific gene expression. Here we performed simultaneous genome-wide DNA methylation and gene expression analysis on purified intestinal epithelial cells derived from human fetal gut, healthy pediatric biopsies, and children newly diagnosed with inflammatory bowel disease (IBD). Results were validated using pyrosequencing, real-time PCR, and immunostaining. The functional impact of DNA methylation changes on gene expression was assessed by employing in-vitro assays in intestinal cell lines. DNA methylation analyses allowed identification of 214 genes for which expression is regulated via DNA methylation, i.e. regulatory differentially methylated regions (rDMRs). Pathway and functional analysis of rDMRs suggested a critical role for DNA methylation in regulating gene expression and functional development of the human intestinal epithelium. Moreover, analysis performed on intestinal epithelium of children newly diagnosed with IBD revealed alterations in DNA methylation within genomic loci, which were found to overlap significantly with those undergoing methylation changes during intestinal development. Our study provides novel insights into the physiological role of DNA methylation in regulating functional maturation of the human intestinal epithelium. Moreover, we provide data linking developmentally acquired alterations in the DNA methylation profile to changes seen in pediatric IBD.
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Chen J, Ren JA, Han G, Gu GS, Wang GF, Wu XW, Zhou B, Hu D, Wu Y, Zhao YZ, Li JS. Polymorphism of heat shock protein 70-2 and enterocutaneous fistula in Chinese population. World J Gastroenterol 2014; 20:12559-65. [PMID: 25253958 PMCID: PMC4168091 DOI: 10.3748/wjg.v20.i35.12559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 04/08/2014] [Accepted: 06/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether the heat shock protein 70-2 (HSP70-2) polymorphism is associated with enterocutaneous fistulas in a Chinese population. METHODS This study included 131 patients with enterocutaneous/enteroatmospheric fistulas. Patients with inflammatory bowel disease or other autoimmune diseases were excluded from this study. All patients with enterocutaneous/enteroatmospheric fistulas were followed up for three months to observe disease recurrence. In addition, a total of 140 healthy controls were also recruited from the Jinling Hospital, matched according to the sex and age of the patient population. Genomic DNA was extracted from peripheral blood from each participant. The HSP70-2 restriction fragment length polymorphism related to the polymorphic PstI site at position 1267 was characterized by polymerase chain reaction (PCR). First PCR amplification was carried out, and then PCR products were digested with PstI restriction enzyme. The DNA lacking the polymorphic PstI site within HSP70-2 generates a product of 1117 bp in size (allele A), whereas the HSP70-2 PstI polymorphism produces two fragments of 936 bp and 181 bp in size (allele B). RESULTS The frequency of the HSP70-2 PstI polymorphism did not differ between patients and controls; however, the A allele was more predominant in patients with enterocutaneous fistulas than in controls (60.7% vs 51.4%, P = 0.038, OR = 1.425, 95%CI: 1.019-1.994). Sixty-one patients were cured by a definitive operation, drainage operation, or percutaneous drainage while 52 patients were cured by nonsurgical treatment. There was no significant difference in the frequency of the HSP70-2 PstI polymorphism between the patients who had surgery compared to those who did not (P = 0.437, OR = 1.237, 95%CI: 0.723-2.117). Moreover, 11 patients refused any treatment for economic reasons or tumor burden, and 7 patients with enterocutaneous fistulas (5.8%) died during the follow-up period. However, there was no significant difference in the frequency of the HSP70-2 PstI polymorphism between the patients who survived compared to those who died (P = 0.403, OR = 0.604, 95%CI: 0.184-1.986). CONCLUSION The A allele of the HSP70-2 PstI polymorphism was associated with enterocutaneous fistulas in this Chinese population.
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Sarlos P, Kovesdi E, Magyari L, Banfai Z, Szabo A, Javorhazy A, Melegh B. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature. World J Gastrointest Pathophysiol 2014; 5:304-21. [PMID: 25133031 PMCID: PMC4133528 DOI: 10.4291/wjgp.v5.i3.304] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/19/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.
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Chen J, Ren J, Gu G, Wang G, Wu X, Yan D, Liu S, Li J. Crohn's disease and polymorphism of heat shock protein gene HSP70-2 in the Chinese population. J Gastroenterol Hepatol 2013; 28:814-8. [PMID: 23425104 DOI: 10.1111/jgh.12163] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/03/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Crohn's disease (CD) is a multifactorial disorder with a pivotal role of the genetic component. A single nucleotide polymorphism in heat shock protein 70-2 (HSP70-2) has been shown to be associated with a severe clinical course in CD. The purpose of this study was to identify associations between the HSP70-2 polymorphism and the clinical courses of CD in the Chinese population. METHODS One hundred patients with CD and 190 healthy individuals were genotyped for the HSP70-2 PstI polymorphism by restriction fragment length polymorphism analysis. RESULTS The genotype frequency of the PstI polymorphism did not differ between patients and controls. The A allele was higher in CD patients than in controls (61% vs 52%, P = 0.047, odds ratio [OR] = 1.423, 95% confidence interval [CI]: 1.004-2.015). Furthermore, this polymorphism was higher in the penetrating or fistula surgery of CD patients than in controls (63% vs 52%, P = 0.049, OR = 1.530, 95% CI: 1.001-2.337; Table ). But there was no significant difference between the penetrating or fistula surgery patients and no surgery patients (P = 0.673, OR = 0.883, 95% CI: 0.495-1.574). We used multivariate analysis to determine the effects of genotypes on sex, disease behavior, disease location, and so on. No significant difference was observed between these parameters and genotype. CONCLUSION This study reported that the allele A of PstI polymorphism was the association between CD and HSP70-2 gene in the Chinese population. It was also association between penetrating or fistula surgery of CD and HSP70-2 gene in the Chinese population.
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Affiliation(s)
- Jun Chen
- The Research Institute of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
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12
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Iezzi LE, Feitosa MR, Medeiros BA, Aquino JC, Almeida ALNRD, Parra RS, Rocha JJRD, Féres O. Crohn's disease and hyperbaric oxygen therapy. Acta Cir Bras 2011; 26 Suppl 2:129-132. [PMID: 22030829 DOI: 10.1590/s0102-86502011000800024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
PURPOSE Evaluate the application of Hyperbaric Oxygen Therapy (HBO) in patients with Crohn's disease (CD) refractory to pharmacologic therapy, who developed abdominal, anorectal or skin complications. METHODS Fourteen selected patients with refractory CD and treated at the School of Medicine of Ribeirao Preto, University of Sao Paulo (FMRP-USP) and at the Center of Hyperbaric Medicine, São Paulo Hospital (CEMEHI) were submitted to HBO. RESULTS Of the 14 patients evaluated, 11 had a satisfactory response. CONCLUSION HBO has shown benefits in patients with CD refractory to pharmacologic therapy.
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Yamamoto-Furusho JK, Rodríguez-Bores L, Granados J. HLA-DRB1 alleles are associated with the clinical course of disease and steroid dependence in Mexican patients with ulcerative colitis. Colorectal Dis 2010; 12:1231-5. [PMID: 19674023 DOI: 10.1111/j.1463-1318.2009.02025.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The aim of this study was to study the association between the HLA-DRB1 alleles and the clinical course of ulcerative colitis (UC). METHOD Seventy-five Mexican patients with UC were studied. High resolution HLA typing was performed using Polymerase Chain Reaction-Sequence Specific Oligonucleotide PCR-SSO reverse dot blot and Polymerase Chain Reaction-single specific primer PCR-SSP. Molecular typing techniques were applied to define HLA-DRB1 alleles. RESULTS Seventy-five patients (36 female patients, 39 male patients) were studied. Significant associations were found between some HLA-DRB1 alleles and the clinical course of disease: initial active and then inactive and the HLA-DRB1*14 allele (P = 0.03; OR = 4.63; 95% CI: 1.08-21.23); and HLA-DRB1*08 allele (P = 0.04; OR = 4.34; 95% CI: 1.9-33.3). On the other hand, the HLA-DRB1*07 (P = 0.001; OR = 9.76 95% CI: 1.55-65.56) was significantly associated with steroid dependence in UC patients. CONCLUSIONS This study suggests that HLA-DRB1 alleles were associated with the clinical course of disease and steroid dependence in UC patients.
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Affiliation(s)
- J K Yamamoto-Furusho
- Department of Gastroenterology, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico.
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Limdi JK, Siminovitch KA, Newman W. Genetic dissection of inflammatory bowel disease: unravelling etiology and improving diagnostics. Expert Rev Clin Immunol 2010; 1:609-17. [PMID: 20477602 DOI: 10.1586/1744666x.1.4.609] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Over the past 10 years, remarkable advances in the mapping and identification of genes involved in susceptibility to inflammatory bowel disease have been witnessed. Most notable among these advances has been the discovery of variants in the CARD15, DLG5, SLC22A4 and SLC22A5 genes, which are associated with increased risk of inflammatory bowel disease or specifically Crohn's disease. These discoveries have provided critical new insights into the molecular pathophysiology of inflammatory bowel disease and the pathways wherein genetic and environmental factors such as enteric bacterial flora may interact to trigger immune dysregulation and intestinal inflammation. This review will outline the discovery of these inflammatory bowel disease-related genes, describe future prospects for further inflammatory bowel disease gene identification, and consider the impact of a genetic understanding of inflammatory bowel disease on future clinical practice.
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Affiliation(s)
- Jimmy K Limdi
- Wythenshawe Hospital, South Manchester University Hospitals, NHS Trust, Manchester, UK.
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15
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Bossa F, Colombo E, Andriulli A, Annese V. Treatment of steroid-naive ulcerative colitis. Expert Opin Pharmacother 2009; 10:1449-1460. [PMID: 19445560 DOI: 10.1517/14656560902973728] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The introduction of steroid therapy by Truelove and Witts in the 1950s revolutionized the treatment of ulcerative colitis. Corticosteroids are potent inhibitors of T-cell activation and proinflammatory cytokines and still represent the mainstay of therapy of patients with ulcerative colitis. About 15% of patients are resistant to steroids, and about a quarter of patients become dependent within 1 year of therapy. Steroid-related adverse events are numerous and occur frequently. So, new steroids with low systemic absorption and better safety profile have been studied, but they show an overall lower efficacy compared with traditional steroids. A new drug-delivery system based on the use of autologous erythrocytes loaded with dexamethasone 21-phosphate has been recently developed. Several studies have demonstrated its efficacy in steroid-dependent patients leading to complete withdrawal of oral steroids and disappearance of the most steroid-related adverse events. In this review we elaborate on the role of steroids in the treatment of ulcerative colitis, focusing on the aspects related to the mechanisms of action and resistance to the steroids, and their secondary effects. Moreover, we analyse the alternatives to traditional systemic steroids such as the new steroids with low bioavailability and the steroids encapsulated into erythrocytes.
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Affiliation(s)
- Fabrizio Bossa
- Casa Sollievo della Sofferenza Hospital - IRCCS, Unit of Gastroenterology and Digestive Endoscopy, Viale Cappuccini 1, 71013 San Giovanni Rotondo (FG), Italy.
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16
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Cassinotti A, Birindelli S, Clerici M, Trabattoni D, Lazzaroni M, Ardizzone S, Colombo R, Rossi E, Porro GB. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009; 104:195-217; quiz 194, 218. [PMID: 19098870 DOI: 10.1038/ajg.2008.10] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The human leukocyte antigen (HLA) system includes genes involved in graft-vs-host rejection and in immune response. The discovery that HLAs are associated with several diseases led to appealing developments both in basic biomedical research and in clinical medicine, and offered the opportunity to improve the understanding of pathogenesis and classification of diseases, as well as to provide diagnostic and prognostic indicators. The aim of this article is to review the association between HLA alleles and autoimmune digestive disease and its current relationship with modern HLA nomenclature and clinical practice. METHODS Articles dealing with the association between HLAs and autoimmune digestive disease (including celiac disease, inflammatory bowel disease, autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis) were searched for using Pubmed and SCOPUS databases from earliest records to January 2008. RESULTS The review has provided two sections. In the first, we explain the basic principles of HLA structure, function, and nomenclature, as an introduction to the second section, which describes current associations between HLA alleles and digestive diseases. The clinical implications of each HLA association are critically discussed. Actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease. CONCLUSIONS The knowledge of current HLA nomenclature and of its association with some digestive diseases such as celiac disease can be useful in clinical practice for diagnostic and prognostic purposes. This can avoid improper HLA typing as well as stressing the need for further studies on other possible clinical applications.
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Affiliation(s)
- Andrea Cassinotti
- Department of Clinical Science, Division of Gastroenterology, L. Sacco University Hospital, via G.B.Grassi 74, Milan, Italy.
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Tilakaratne WM, Freysdottir J, Fortune F. Orofacial granulomatosis: review on aetiology and pathogenesis. J Oral Pathol Med 2008; 37:191-5. [PMID: 18321344 DOI: 10.1111/j.1600-0714.2007.00591.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Orofacial granulomatosis (OFG) is considered as an uncommon disease and nomenclature of the disease was subjected to debate for a long time. Although various aetiological agents such as food substances, food additives, dental materials and various microbiological agents have been implicated in the disease process its precise pathogenesis is yet to be elucidated. Delayed type of hypersensitivity reaction appears to play a significant role, although the exact antigen inducing the immunological reaction varies in individual patients. However, evidence for the role of genetic predisposition to the disease is sparse. The underlying immunological mechanism appears to show some similarities between OFG and Crohn's disease, emphasizing the need for more comparative studies of the two entities. Therefore, we propose the term idiopathic OFG as a better term for those cases restricted to oral region without any identifiable known granulomatous disease and the diagnosis should not be changed until the patient develops systemic manifestations of a specific granulomatous condition. This review attempts to discuss the role of different aetiological agents and certain aspects of pathogenesis of OFG.
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Affiliation(s)
- W M Tilakaratne
- Centre for Research in Clinical and Diagnostic Oral Sciences, The School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
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Weersma RK, van Dullemen HM, van der Steege G, Nolte IM, Kleibeuker JH, Dijkstra G. Review article: Inflammatory bowel disease and genetics. Aliment Pharmacol Ther 2007; 26 Suppl 2:57-65. [PMID: 18081650 DOI: 10.1111/j.1365-2036.2007.03476.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn's disease (CD) is multigenic disorder. Tremendous progress has been achieved in unravelling the genetic background of IBD. It has led to the discovery of mutations in NOD2 associated with ileal CD and numerous other genes have been found to be associated with IBD susceptibility. METHODS A review of the literature on the genetic background of IBD was performed. RESULTS It is only partially understood how mutations in NOD2 lead to CD. Mouse models, in vitro data and studies in humans offer conflicting data as regards whether there is a loss or gain of function of NOD2 in CD. Several additional genes have been identified of which only a few are currently being recognized as potential disease causing or disease modifying genes. Promising candidate genes include TLR4, MDR1, NOD1 (CARD4), DLG5 as well as the IBD5 locus including SLC22A4/5. CONCLUSIONS Although genetic research has not yet led to a better prediction of the disease course or patient selection for medical therapy, remarkable progress has been made in the understanding of the pathogenesis of IBD. For future genetic research, accurate phenotyping of patients is very important and large population-based cohorts are needed. Eventually, genetic research may be able to classify different disease phenotypes on a more detailed molecular basis and may provide important contributions in the development of new therapeutic approaches.
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Affiliation(s)
- R K Weersma
- Department of Gastroenterology and Hepatology, Section Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
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Gómez-García M, Oliver J, Márquez A, Mendoza JL, López-Nevot MA, Fernández-Arquero M, González-Escribano MF, Díaz-Rubio M, de la Concha EG, Urcelay E, Martín J, Martínez A. Strong protective effect of DR3 against ulcerative colitis in the Spanish population. Am J Gastroenterol 2007; 102:2762-6. [PMID: 17714554 DOI: 10.1111/j.1572-0241.2007.01487.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon. Major histocompatibility complex (MHC) on the short arm of human chromosome 6 has been thoroughly studied as a susceptibility locus. However, one of the strongest MHC associations found, that of HLA-DR3 with UC protection, has not been observed in all populations. Our aim in the present study was to evaluate this negative association in a large cohort of Spanish UC patients and controls, and to try to elucidate which, if any, of the diverse DR3 haplotypes (identified by TNFa and b microsatellites, located in the MHC class III region) is most tightly associated (negatively) with the disease. METHODS A total of 537 UC patients and 748 healthy controls from Spain were included in the present study. Low-resolution DR genotyping was performed by PCR and hybridization with allele-specific oligonucleotide probes. TNFa and b microsatellites were studied in a subset of samples (279 UC patients and 503 healthy controls) by PCR followed by capillary electrophoresis. DR-TNFa-TNFb haplotypes were estimated by the expectation-maximization algorithm and comparisons were performed by a chi2 test. RESULTS After a stepwise procedure, the only DR alleles significantly associated with the disease were DR3 (very strongly, protection) and DR4 (weakly, protection). The strong protective effect of DR3 was evenly distributed among the haplotypes DR3-TNFa1b5, DR3-TNFa2b3, and DR3-TNFother. CONCLUSIONS Our results confirm the strong protective effect of DR3 in our population, and suggest that the relevant protective gene is located centromeric to TNFa and TNFb markers in the MHC region.
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Schaffer T, Müller S, Flogerzi B, Seibold-Schmid B, Schoepfer AM, Seibold F. Anti-Saccharomyces cerevisiae mannan antibodies (ASCA) of Crohn's patients crossreact with mannan from other yeast strains, and murine ASCA IgM can be experimentally induced with Candida albicans. Inflamm Bowel Dis 2007; 13:1339-46. [PMID: 17636567 DOI: 10.1002/ibd.20228] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Anti-Saccharomyces cerevisiae antibodies (ASCA) present in a subgroup of Crohn's disease (CD) patients indicate loss of tolerance against commensal antigens. ASCA can be induced in Candida albicans-infected rabbits, suggesting their potential crossreactive nature. The present study aimed to determine crossreactivities of ASCA with cell wall mannans from other yeasts, including the opportunistic pathogen C. albicans, and to define the requirements for (crossreactive) ASCA in experimental mice. METHODS ASCA were determined by enzyme-linked immunosorbent assay (ELISA). ASCA were neutralized by preincubating sera with purified mannans. Binding of ASCA was visualized by Western blot. Mice were immunized with live yeasts and experimental colitis was induced with dextran sodium sulfate (DSS). RESULTS Seroreactivity of ASCA-positive CD patients against S. cerevisiae mannan significantly correlates with that against mannans from 5 other yeast species, including C. albicans. This correlation is due to crossreactive IgG, demonstrated by the loss of reactivity after preincubation of sera with mannans from the other yeasts. Immunization of mice with S. cerevisiae or C. albicans fails to induce (crossreactive) ASCA IgM or IgG antibodies. Subsequent chronic experimental colitis concomitant with feeding live yeasts promotes ASCA IgM but not IgG generation, while titers remain modest compared to those in ASCA-positive CD patients. CONCLUSIONS Correlations of ASCA reactivities against mannans from different yeasts are due to crossreactive IgGs. The inability of mice to readily generate ASCA is in line with the current opinion that genetic predisposition is a prerequisite for the development of this and other unusual immune reactivities in CD.
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Affiliation(s)
- Thomas Schaffer
- Department of Clinical Research, Division of Gastroenterology, University Hospital Bern, University of Bern, Bern, Switzerland
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22
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Roy N, Barnett M, Knoch B, Dommels Y, McNabb W. Nutrigenomics applied to an animal model of Inflammatory Bowel Diseases: transcriptomic analysis of the effects of eicosapentaenoic acid- and arachidonic acid-enriched diets. Mutat Res 2007; 622:103-16. [PMID: 17574631 DOI: 10.1016/j.mrfmmm.2007.04.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2007] [Revised: 03/30/2007] [Accepted: 04/12/2007] [Indexed: 01/07/2023]
Abstract
In vivo models of Inflammatory Bowel Diseases (IBD) elucidate important mechanisms of chronic inflammation. Complex intestinal responses to food components create a unique "fingerprint" discriminating health from disease. Five-week-old IL10(-/-) and C57BL/6J (C57; control) mice were inoculated orally with complex intestinal microflora (CIF) and/or pure cultures of Enterococcus faecalis and E. faecalis (EF) aiming for more consistent inflammation of the intestinal mucosa. Inoculation treatments were compared to non-inoculated IL10(-/-) and C57 mice, either kept in specific pathogen free (SPF) or conventional conditions (2x5 factorial design). At 12 weeks of age, mice were sacrificed for intestinal histological (HIS) and transcriptomic analysis using limma and Ingenuity Pathway Analysis Software. Colonic HIS was significantly affected (P<0.05) in inoculated IL10(-/-) mice and accounted for approximately 60% of total intestinal HIS. Inoculation showed a strong effect on colonic gene expression, with more than 2000 genes differentially expressed in EF.CIF-inoculated IL10(-/-) mice. Immune response gene expression was altered (P<0.05) in these mice. The second study investigated the effect of arachidonic (AA) and eicosapentaenoic acid (EPA) on colonic HIS and gene expression to test whether EPA, contrary to AA, diminished intestinal inflammation in EF.CIF IL10(-/-) mice (2 x 4 factorial design). AIN-76A (5% corn oil) and AIN-76A (fat-free) +1% corn oil supplemented with either 3.7% oleic acid (OA), AA or EPA were used. IL10(-/-) mice fed EPA- and AA-enriched diets had at least 40% lower colonic HIS (P<0.05) than those fed control diets (AIN-76A and OA diets). The expression of immune response and 'inflammatory disease' genes (down-regulated: TNFalpha, IL6, S100A8, FGF7, PTGS2; up-regulated: PPARalpha, MGLL, MYLK, PPSS23, ABCB4 with EPA and/or AA) was affected in IL10(-/-) mice fed EPA- and AA-enriched diets, compared to those fed AIN-76A diet.
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Affiliation(s)
- Nicole Roy
- Food, Metabolism & Microbiology Section, Food & Health Group, AgResearch Grasslands, Palmerston North, New Zealand.
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Cholongitas E, Papatheodoridis GV, Zappoli P, Giannakopoulos A, Patch D, Marelli L, Shusang V, Kalambokis G, Shirling G, Rolando N, Burroughs AK. Combined HLA-DR and -DQ disparity is associated with a stable course of ulcerative colitis after liver transplantation for primary sclerosing cholangitis. Liver Transpl 2007; 13:552-7. [PMID: 17394153 DOI: 10.1002/lt.21077] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Combined disparity of human leukocyte antigen (HLA)-DR and -DQ between mother and fetus is associated with less severe ulcerative colitis (UC) during pregnancy. We evaluated whether donor-recipient HLA disparity after liver transplantation (LT) affects UC in patients with primary sclerosing cholangitis (PSC). Sixty-nine consecutive patients with PSC underwent LT; all underwent colonoscopy before LT; 48 had UC before and 3 had de novo UC after LT. Clinical and laboratory data, activity and treatment of UC, post-LT cytomegalovirus infection, and disparity of HLA-A, -B, -DR, and -DQ for each donor-recipient pair were evaluated. Pre-LT quiescent UC was present in 26 patients. Post-LT UC activity was evaluated in 36 of 51 patients with UC who had not undergone pre-LT colectomy and who had >12 months' post-LT survival. Of these, 16 were stable, 17 had worsened, and 3 had de novo UC. Seven required colectomy (4 for dysplasia or cancer) after LT. Post-LT cytomegalovirus viremia was neither associated with worse UC activity (P = 0.58) nor de novo UC. Disparity with respect to HLA-A, -B, -DR, and -DQ was found in 58%, 27%, 44%, and 39% donor-recipient pairs, respectively. Post-LT UC course was similar with respect to single HLA disparity. However, disparity in none or only one HLA-DR or -DQ was significantly associated with worse activity compared with patients with disparity at both (65% vs. 0%, P = 0.009). Logistic regression found that the disparity for both -DR and -DQ was the only factor statistically significantly associated with post-LT UC activity. We conclude that disparity in both HLA-DR and -DQ between donor and recipient is associated with stable UC activity after LT.
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Affiliation(s)
- Evangelos Cholongitas
- Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, Hampstead, London, UK
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Karlsen TH, Boberg KM, Vatn M, Bergquist A, Hampe J, Schrumpf E, Thorsby E, Schreiber S, Lie BA. Different HLA class II associations in ulcerative colitis patients with and without primary sclerosing cholangitis. Genes Immun 2007; 8:275-8. [PMID: 17301827 DOI: 10.1038/sj.gene.6364377] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2006] [Revised: 01/11/2007] [Accepted: 01/12/2007] [Indexed: 12/17/2022]
Abstract
Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have inflammatory bowel disease (IBD), the majority ulcerative colitis (UC). An inherent problem in interpreting positive findings in genetic association studies of PSC is thus to distinguish between factors associated with hepatobiliary versus intestinal pathology. We aimed to clarify to what extent human leukocyte antigen (HLA) class II associations in UC patients with and without PSC differ. High-resolution DRB1 and DQB1 typing was performed in 365 Scandinavian PSC patients, an independent cohort of 330 Norwegian UC patients and 368 healthy controls. HLA associations found in PSC were mostly distinct from those seen in UC, and no significant differences were noted between PSC patients with concurrent UC and PSC patients without IBD. This suggests different HLA associated genetic susceptibility to PSC and UC, and supports notions that UC in PSC may represent a distinct UC phenotype.
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Affiliation(s)
- T H Karlsen
- Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway.
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Zouiten-Mekki L, Karoui S, Kharrat M, Fekih M, Matri S, Boubaker J, Filali A, Chaabouni H. Crohn's disease and polymorphism of heat shock protein gene HSP70-2 in the Tunisian population. Eur J Gastroenterol Hepatol 2007; 19:225-8. [PMID: 17301649 DOI: 10.1097/01.meg.0000252625.65549.29] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIMS Crohn's disease is a multifactorial disorder with a pivotal role of the genetic component. HSP70-2 gene, located in IBD3 region, has a PstI polymorphic site associated recently with Crohn's disease especially with a perforating form. In this study, we sought to determine whether this polymorphism was associated with Crohn's disease in the Tunisian population and its correlation with clinical manifestation of the disease. METHODS In all, 148 patients with Crohn's disease and 81 healthy individuals were genotyped for the HSP70-2 PstI polymorphism by restriction fragment length polymorphism analysis. RESULTS The allele and genotype frequency of the PstI polymorphism did not differ between patients and controls. Furthermore, this polymorphism was not associated with specific disease behavior. CONCLUSION This study reported the absence of association between Crohn's disease and HSP70-2 gene in the Tunisian population. The allele A of PstI polymorphism was not associated with phenotype of the disease.
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Cucchiara S, Latiano A, Palmieri O, Canani RB, D'Incà R, Guariso G, Vieni G, De Venuto D, Riegler G, De'Angelis GL, Guagnozzi D, Bascietto C, Miele E, Valvano MR, Bossa F, Annese V. Polymorphisms of tumor necrosis factor-alpha but not MDR1 influence response to medical therapy in pediatric-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44:171-179. [PMID: 17255827 DOI: 10.1097/mpg.0b013e31802c41f3] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIM We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms -G308A and -C857T of the TNF-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy. RESULTS The frequency of the -308A allele of the TNF-alpha gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the -C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the -308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression. CONCLUSIONS In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection.
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Walters TD, Silverberg MS. Genetics of inflammatory bowel disease: current status and future directions. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 20:633-9. [PMID: 17066152 PMCID: PMC2660789 DOI: 10.1155/2006/326025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Thomas D Walters
- Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario
| | - Mark S Silverberg
- Department of Medicine, Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario
- Correspondence: Dr Mark S Silverberg, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Room 441, 600 University Avenue, Toronto, Ontario M5G 1X5. Telephone 416-586-8236, fax 416-586-4878, e-mail
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Turner D, Walsh CM, Steinhart AH, Griffiths AM. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol 2007; 5:103-10. [PMID: 17142106 DOI: 10.1016/j.cgh.2006.09.033] [Citation(s) in RCA: 447] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Colectomy is a potentially life-saving procedure for patients with severe attacks of UC who fail medical therapy. We aimed to systematically review studies that reported the short-term colectomy rate in severe UC or reported variables that could predict treatment failure. METHODS We conducted a systematic literature search for cohort studies and controlled trials published between 1974-2006. RESULTS Thirty-two studies met the inclusion criteria; 16 reported short-term outcome and predictors of therapy failure, 13 only outcome, and 3 only predictors. In the pooled analysis, 581 of 1991 patients required colectomy (weighted mean 27; 95% confidence interval [CI], 26%-28%), and 22 died (1%; 95% CI, 0.7%-1.5%). In a heterogeneity-controlled meta-regression, colectomy rate did not change during the last 30 years (R(2) = 0.07, P = .8). Cyclosporine was used in only 100 patients, with a 51% (95% CI, 41%-60%) short-term success rate. A second meta-regression failed to demonstrate a dose-colectomy response of methylprednisolone therapy beyond 60 mg daily (R(2) < 0.01, P = .98). More than 20 variables were identified in 19 studies to predict medical therapy failure, but only a few were consistently reproduced: disease extent, stool frequency, temperature, heart rate, C-reactive protein, albumin, and radiologic assessment. CONCLUSIONS The short-term colectomy rate in severe UC has remained stable during the last 30 years, despite the introduction of cyclosporine, which was not used frequently. We could not find any support for administering methylprednisolone at a higher dose than 60 mg/day. Variables that predict outcome of corticosteroid therapy could aid in the development of guidelines for introduction of rescue therapies in severe UC.
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Affiliation(s)
- Dan Turner
- Division of Gastroenterology, Hepatology and Nutrition, the Hospital for Sick Children, Toronto, Canada
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Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 2007; 39:177-99. [PMID: 17457716 DOI: 10.1080/07853890701197615] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
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Affiliation(s)
- Philippe Goyette
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
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31
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Ikeda Y, Migita K, Ito M, Miyazato M, Okamoto K, Eguchi K, Ishibashi H, Shikuwa S. A Case of Classical Polyarteritis Nodosa Complicated by Ulcerative Colitis. Am J Med Sci 2006; 332:137-9. [PMID: 16969144 DOI: 10.1097/00000441-200609000-00008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Classical polyarteritis nodosa (PAN) is a term that includes patients with necrotizing inflammation of medium-sized arteries and excludes those with microscopic vessel involvement. Although gastrointestinal manifestations are not unusual in patients with classical PAN, the association with ulcerative colitis has been reported only rarely. We describe a patient with classical PAN complicated by bilateral renal artery aneurysms with subsequent rapture and perirenal hemorrhages. He was successfully treated, and the bilateral renal aneurysms resolved with steroid therapy. Two years later, the patient presented with hematochezia. Colonoscopy revealed inflamed rectal mucosa with bleeding ulcers. Histologic findings of biopsy specimens showed severe mucosal inflammation and crypt abscess. The patient was diagnosed with ulcerative colitis, and the symptoms attenuated after meselazine therapy.
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Affiliation(s)
- Yukiko Ikeda
- Department of Gastroenterology, NHO National Nagasaki Medical Center, Nagasaki, Japan
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32
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Török HP, Glas J, Lohse P, Folwaczny C. Genetic variants and the risk of Crohn's disease: what does it mean for future disease management? Expert Opin Pharmacother 2006; 7:1591-602. [PMID: 16872262 DOI: 10.1517/14656566.7.12.1591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Genetic research in inflammatory bowel disease, especially in Crohn's disease, has made significant progress during recent years. There have been > 10 total genome scans that have been performed, and susceptibility loci on several chromosomes have been identified. Together with candidate gene studies, these scans have led to the identification of several susceptibility genes, with CARD15 being the most important. These genetic data have already provided important insights into the pathophysiology of inflammatory bowel disease and are stimulating future research. On the other hand, genotype-phenotype associations have illustrated the heterogenic nature of the disease. Although the clinical application of this knowledge is so far limited, there is significant optimism that an individual management of patients based on genetic data will be possible in the near future.
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Affiliation(s)
- Helga-Paula Török
- Department of Surgery Innenstadt, Ludwig-Maximilians University, Nussbaumstrasse 20, D-80336 Munich, Germany.
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Abstract
Inflammatory bowel diseases are associated with extraintestinal manifestations involving almost every organ system in the body. They occur in approximately 20% to 40% of patients with inflammatory bowel diseases. Immune-related and genetic mechanisms play an important role in the pathogenesis of these complications. Peripheral arthritis, erythema nodosum, and episcleritis respond to the treatment of the underlying intestinal inflammation, whereas axial arthropathy, pyoderma gangrenosum, and uveitis do not. Immunomodulator therapy, particularly with biologic agents has been shown to be effective in treating some of the extraintestinal manifestations. Early recognition and treatment are crucial in preventing major morbidity.
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Affiliation(s)
- Sripathi R Kethu
- Department of Medicine, Division of Gastroenterology, Brown Medical School, Providence, RI 02912, USA.
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34
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Lü M, Xia B. Polymorphism of HLA-DRB1 gene shows no strong association with ulcerative colitis in Chinese patients. Int J Immunogenet 2006; 33:37-40. [PMID: 16426241 DOI: 10.1111/j.1744-313x.2005.00559.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The genetic factors predisposing to ulcerative colitis (UC) have remained totally unclear to date. This study aimed to investigate the role of HLA-DRB1 genetic polymorphism in the susceptibility to develop UC in Chinese patients. HLA-DRB1 genotyping was carried out in 72 unrelated patients with UC and 314 healthy controls by using polymerase chain reaction-sequence-specific primers (PCR-SSP). All of the patients and healthy controls are Han people in China. The frequency of DRB1*07 allele was increased in UC patients compared with healthy controls (19.4% vs. 9.2%, P = 0.0229, OR = 2.372, 95%CI: 1.181-4.766), but the significance disappeared when given Bonferroni correction (P(C) = 0.2977). Furthermore, compared with healthy controls, although HLA-DRB1*07, DRB1*16/DRB1*09 and DRB1*07/DRB1*12 genotypes were increased in frequency in the patients with extensive colitis, and the patients without extraintestinal manifestations (EIMs) carried an increased frequency of HLA-DRB1*07 and DRB1*07/DRB1*12 genotypes, these differences did not reach statistical significance after Bonferroni correction. HLA-DRB1 alleles showed no strong association with UC, and no HLA-DRB1 alleles or genotypes were strongly associated with clinical subgroups of UC in Chinese patients.
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Affiliation(s)
- M Lü
- Departments of Internal Medicine & Geriatrics, Zhongnan Hospital, PR China
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Zwiers A, Bouma G. Recent advances in the etiology and treatment of inflammatory bowel disease. Expert Rev Clin Immunol 2006; 2:245-56. [PMID: 20477075 DOI: 10.1586/1744666x.2.2.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Crohn's disease and ulcerative colitis, together comprising the inflammatory bowel diseases, currently affect up to 2 million people in the western developed countries. The pathogenesis of the disease is a complex one in which genetic, immunogenic, microbial and environmental factors contribute to the etiology of the disease. Recent advances in understanding the molecular mechanisms that determine this complex entity have provided insight for promising new therapies.
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Affiliation(s)
- A Zwiers
- Dept of Gastroenterology, Vrije Universiteit Medical Center, Van der Boechorststraat 7, Room J391, 1081 BT Amsterdam, The Netherlands.
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Ding Y, Xia B, Lü M, Zhang Y, Li J, Ye M, Luo H, Yu J, Zhang X, Tan J. MHC class I chain-related gene A-A5.1 allele is associated with ulcerative colitis in Chinese population. Clin Exp Immunol 2005; 142:193-8. [PMID: 16178876 PMCID: PMC1809485 DOI: 10.1111/j.1365-2249.2005.02907.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The human MHC class I chain-related gene A (MICA) plays a role in regulating protective responses by intestinal epithelial Vdelta1 gamma delta T cells and the polymorphism of MICA were reported to be related to several autoimmune diseases. The present study aimed to investigate the association of the microsatellite polymorphisms of TM region of MICA gene with the susceptibility to ulcerative colitis (UC) in Chinese population. The microsatellite polymorphisms of the MICA were genotyped in unrelated 86 Chinese patients with UC and 172 ethnically matched healthy controls by a semiautomatic fluorenscently labelled PCR method. All the subjects were the Chinese with Han nationality. The frequency of MICA-A5.1 homozygous genotype and A5.1 allele were significantly increased in UC patients compared with healthy controls (22.1%versus 7%, P = 0.0009, Pc = 0.0126, OR = 3.781, 95%CI: 1.738-8.225 and 30.2%versus 17.4%, P = 0.0014, Pc = 0.007, OR = 2.051, 95%CI: 1.336-3.148, respectively). Adjusted the effects of gender and age at onset, MICA-A5.1 homozygous genotype and A5.1 allele were also increased in the UC patients. Moreover MICA-A5.1 allele was significantly increased in frequency in the female UC patients (38.2%versus 21.0%, P = 0.0095, Pc = 0.0475, OR = 2.326, 95%CI: 1.234-4.382). Logistic regression analysis also revealed that gender was independently associated with UC patients carried MICA-A5.1 allele (P = 0.046, OR (male) = 0.511, 95% CI: 0.264-0.987). Although the UC patients with extensive colitis (32.5%versus 17.4% in the healthy controls, P = 0.005, Pc = 0.025) and the UC patients with extraintestinal manifestations (36%versus 17.4% in the healthy controls, P = 0.0039, Pc = 0.0195) were more likely to carry the MICA-A5.1 allele, EIMs was associated with extent of disease (P < 0.0001, OR (with EIMs) = 3.511, 95% CI 1.747-7.056) and MICA-A5.1 allele was not associated with UC patients with extensive colitis or with EIMs in the logistic regression analysis. Therefore, the MICA-A5.1 homozygous genotype and A5.1 allele were closely associated with UC and the MICA-A5.1 allele was positively associated with the female UC patients in Chinese population.
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Affiliation(s)
- Yijuan Ding
- Department of Gastroenterology, Renmin Hospital, Wuhan University School of MedicineWuhan
| | - Bing Xia
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
- Department of Key Laboratory of Allergy and Immune Related Diseases, Wuhan University School of MedicineWuhan
| | - Min Lü
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Yan Zhang
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Jin Li
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Mei Ye
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital, Wuhan University School of MedicineWuhan
| | - Jieping Yu
- Department of Gastroenterology, Renmin Hospital, Wuhan University School of MedicineWuhan
| | - Xiaolian Zhang
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
| | - Jingquan Tan
- Department of Internal Medicine & Geriatrics, Research Centre of Digestive Diseases of Zhongnan HospitalPeoples Republic of China
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Wagenleiter SEN, Jagiello P, Akkad DA, Arning L, Griga T, Klein W, Epplen JT. On the genetic involvement of apoptosis-related genes in Crohn's disease as revealed by an extended association screen using 245 markers: no evidence for new predisposing factors. J Negat Results Biomed 2005; 4:8. [PMID: 16318629 PMCID: PMC1315346 DOI: 10.1186/1477-5751-4-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2005] [Accepted: 11/30/2005] [Indexed: 12/29/2022] Open
Abstract
Crohn's disease (CD) presents as an inflammatory barrier disease with characteristic destructive processes in the intestinal wall. Although the pathomechanisms of CD are still not exactly understood, there is evidence that, in addition to e.g. bacterial colonisation, genetic predisposition contributes to the development of CD. In order to search for predisposing genetic factors we scrutinised 245 microsatellite markers in a population-based linkage mapping study. These microsatellites cover gene loci the encoded protein of which take part in the regulation of apoptosis and (innate) immune processes. Respective loci contribute to the activation/suppression of apoptosis, are involved in signal transduction and cell cycle regulators or they belong to the tumor necrosis factor superfamily, caspase related genes or the BCL2 family. Furthermore, several cytokines as well as chemokines were included. The approach is based on three steps: analyzing pooled DNAs of patients and controls, verification of significantly differing microsatellite markers by genotyping individual DNA samples and, finally, additional reinvestigation of the respective gene in the region covered by the associated microsatellite by analysing single-nucleotide polymorphisms (SNPs). Using this step-wise process we were unable to demonstrate evidence for genetic predisposition of the chosen apoptosis- and immunity-related genes with respect to susceptibility for CD.
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Affiliation(s)
| | - Peter Jagiello
- Institute for Clinical Molecular Biology, University Schleswig-Holstein, Kiel, Germany
| | - Denis A Akkad
- Department of Human Genetics, Ruhr-University, Bochum, Germany
| | - Larissa Arning
- Department of Human Genetics, Ruhr-University, Bochum, Germany
| | - Thomas Griga
- Department of Gastroenterology, University Hospital Bergmannsheil, Bochum, Germany
| | - Wolfram Klein
- Department of Human Genetics, Ruhr-University, Bochum, Germany
| | - Jörg T Epplen
- Department of Human Genetics, Ruhr-University, Bochum, Germany
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Mendoza JL, Lana R, Taxonera C, Alba C, Izquierdo S, Díaz-Rubio M. [Extraintestinal manifestations in inflammatory bowel disease: differences between Crohn's disease and ulcerative colitis]. Med Clin (Barc) 2005; 125:297-300. [PMID: 16159555 DOI: 10.1157/13078423] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND OBJECTIVE The true prevalence of the extraintestinal manifestations (EM) associated with inflammatory bowel disease (IBD) may vary depending on the geographic area, IBD population, location and duration of the disease, medication and diagnostic accuracy. The aim of this study was determine the prevalence of the major EM of IBD and their differences between Crohn's disease (CD) and ulcerative colitis (UC). PATIENTS AND METHOD A prospective study with a total of 566 patients (295 CD with median follow up 11.6 years [range: 2-32 years] and 271 UC with median follow up 10.4 years [range: 2-36 years]. Data related to the clinical course, EM and laboratory tests were obtained at diagnosis and during follow-up. RESULTS EM related with IBD appeared al least once in 46.6% of the patients. Joints manifestations were the most common EM. The EM were equal frequent in UC (51.5%) as in CD (42.2%). Hepatobiliary manifestations (odds ratio [OR] = 1.91; 95% confidence interval [CI] 1.15-3.16; p = 0.007), venous thromboembolism (OR = 4.26; 95% CI, 1.3-15.4; p = 0.006) and arthralgias (OR = 1.59; 95% CI, 1.01-2.5; p = 0.035) were more frequent in UC than CD. Erythema nodosum (OR = 2.35; 95% CI, 1.13-5.0; p = 0.013) and peripheral arthritis (OR = 1.95; 95% CI, 1.02-3.74; p = 0.029) were more frequent in CD. The prevalences of ocular, and the rest of joint manifestations were not different according to UC or CD. CONCLUSIONS Prevalence of EM in Spanish IBD patients is among the highest ever reported. The distribution of the EM observed is different between CD and UC. It is necessary to know to allow to prompt diagnosis and prevent undesirable complications.
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Affiliation(s)
- Juan Luis Mendoza
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Aparato Digestivo, Hospital Clínico San Carlos, Madrid, Spain.
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Tursi A, Giorgetti GM, Brandimarte G, Elisei W. High prevalence of celiac disease among patients affected by Crohn's disease. Inflamm Bowel Dis 2005; 11:662-6. [PMID: 15973121 DOI: 10.1097/01.mib.0000164195.75207.1e] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recent literature has shown a correlation between Crohn's disease (CD) and celiac disease, but a prospective study has not been performed. Our aim was to evaluate the prevalence of celiac disease in a consecutive series of patients affected by CD, in whom the disease was diagnosed for the first time. METHODS From January to December 2004, we diagnosed 27 patients affected by CD (13 men and 14 women; mean age, 32.3 yrs; range, 16-69 yrs). In all patients, we performed antigliadin, antiendomysium, and antitransglutaminase antibody tests, and the sorbitol H2 breath test evaluation. In case of antibodies and/or sorbitol positivity, esophagogastroduodenoscopy was performed for a small bowel biopsy. RESULTS Antigliadin, antiendomysium, and antitransglutaminase antibody tests were positive in 8/27 (29.63%), 4/27 (14.81%), and 5/27 (18.52%) patients, respectively, whereas the sorbitol H2 breath test was positive in 11/27 (40.74%) patients: all of them underwent esophagogastroduodenoscopy. Nine of 11 patients showed signs of duodenal endoscopic damage, and 5/9 (55.55%) showed histologic features of celiac disease (18.52% of overall CD population studied): 2 showed Marsh IIIc lesions (1 patient affected by ileal CD and 1 affected by ileo-colonic CD), 2 showed Marsh IIIb lesions (all of them affected by ileo-colonic CD), 1 showed a Marsh IIIa lesion (1 patient affected by colonic CD). CONCLUSIONS Prevalence of celiac disease seems to be high among patients affected by CD, and this finding should be kept in mind at the time of the first diagnosis of CD; a gluten-free diet should be promptly started.
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Affiliation(s)
- Antonio Tursi
- Digestive Endoscopy Unit, "Lorenzo Bonomo" Hospital, Andria, Italy.
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Bond JS, Matters GL, Banerjee S, Dusheck RE. Meprin metalloprotease expression and regulation in kidney, intestine, urinary tract infections and cancer. FEBS Lett 2005; 579:3317-22. [PMID: 15943977 DOI: 10.1016/j.febslet.2005.03.045] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2005] [Indexed: 01/28/2023]
Abstract
Meprins are unique plasma membrane and secreted metalloproteinases that are highly regulated at the transcriptional and post-translational levels. Meprin alpha and beta subunits are abundantly expressed in kidney and intestinal epithelial cells, are secreted into the urinary tract and intestinal lumen, and are found in leukocytes and cancer cells under certain conditions. Their location and proteolytic activities indicate functions at the interface of the host and the external environment, and in trafficking of macrophages and metastases of cancer cells. These proteases can be detrimental when there is tissue damage or disruption, as in acute renal injury or intestinal inflammation, and there is evidence they are involved in movement of leukocytes and cancer cells to sites of infection or in metastasis, respectively.
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Affiliation(s)
- Judith S Bond
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Lu KC, Dietz DW. The Genetics of Inflammatory Bowel Disease. SEMINARS IN COLON AND RECTAL SURGERY 2004. [DOI: 10.1053/j.scrs.2005.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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