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Boldyreva LV, Evtushenko AA, Lvova MN, Morozova KN, Kiseleva EV. Underneath the Gut-Brain Axis in IBD-Evidence of the Non-Obvious. Int J Mol Sci 2024; 25:12125. [PMID: 39596193 PMCID: PMC11594934 DOI: 10.3390/ijms252212125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
The gut-brain axis (GBA) plays a pivotal role in human health and wellness by orchestrating complex bidirectional regulation and influencing numerous critical processes within the body. Over the past decade, research has increasingly focused on the GBA in the context of inflammatory bowel disease (IBD). Beyond its well-documented effects on the GBA-enteric nervous system and vagus nerve dysregulation, and gut microbiota misbalance-IBD also leads to impairments in the metabolic and cellular functions: metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton dysregulation. These systemic effects are currently underexplored in relation to the GBA; however, they are crucial for the nervous system cells' functioning. This review summarizes the studies on the particular mechanisms of metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton impairments in IBD. Understanding the involvement of these processes in the GBA may help find new therapeutic targets and develop systemic approaches to improve the quality of life in IBD patients.
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Affiliation(s)
- Lidiya V. Boldyreva
- Scientific-Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia;
| | - Anna A. Evtushenko
- Scientific-Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia;
| | - Maria N. Lvova
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (M.N.L.); (K.N.M.); (E.V.K.)
| | - Ksenia N. Morozova
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (M.N.L.); (K.N.M.); (E.V.K.)
| | - Elena V. Kiseleva
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (M.N.L.); (K.N.M.); (E.V.K.)
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Singh A, Midha V, Kochhar GS, Shen B, Sood A. Management of Perianal Fistulizing Crohn's Disease. Inflamm Bowel Dis 2024; 30:1579-1603. [PMID: 37672347 DOI: 10.1093/ibd/izad195] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Indexed: 09/08/2023]
Abstract
Perianal fistulizing Crohn's disease (CD) represents a severe phenotype of CD that is associated with significant morbidity and reduction in quality of life. Perianal fistulizing CD is caused by a complex interplay of genetic predisposition, immune dysregulation, gut dysbiosis, and various unknown physiological and mechanical factors. A multidisciplinary approach is hence required for optimal management . A detailed anatomical description and classification of perianal fistula, including comprehensive clinical, endoscopic, and radiological diagnostic workup, is an important prerequisite to treatment. For simple perianal fistulas, use of antibiotics and immunomodulators, with or without fistulotomy, are appropriate measures. The medical management of complex perianal fistula, on the other hand, requires adequate control of infection before initiation of therapy with immunomodulators. In active complex perianal fistula, anti-tumor necrosis factors remain the most accepted therapy, with concomitant use of antibiotics or immunomodulators enhancing the efficacy. For patients refractory to anti-tumor necrosis factors, treatment with anti-integrins, anti-interleukins, and small molecules is being evaluated. Mesenchymal stem cells, hyperbaric oxygen therapy, and exclusive enteral nutrition have also been investigated as adjunct therapies. Despite the expansion of the medical armamentarium, a large proportion of the patients require surgical interventions. In this review, we provide an up-to-date overview of the pathophysiology, clinical presentation, diagnosis, and medical management of perianal fistulizing CD. A brief overview of the surgical management of perianal fistulizing CD is also provided.
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Affiliation(s)
- Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, India
| | - Gursimran Singh Kochhar
- Division of Gastroenterology, Hepatology and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA
| | - Bo Shen
- Center for Interventional Inflammatory Bowel Disease, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY, USA
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, India
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Lu H, Suo Z, Lin J, Cong Y, Liu Z. Monocyte-macrophages modulate intestinal homeostasis in inflammatory bowel disease. Biomark Res 2024; 12:76. [PMID: 39095853 PMCID: PMC11295551 DOI: 10.1186/s40364-024-00612-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive. MAIN BODY In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD. CONCLUSION In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.
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Affiliation(s)
- Huiying Lu
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Zhimin Suo
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
| | - Jian Lin
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Yingzi Cong
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China.
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Anandabaskaran S, Hanna L, Iqbal N, Constable L, Tozer P, Hart A. Where Are We and Where to Next?-The Future of Perianal Crohn's Disease Management. J Clin Med 2023; 12:6379. [PMID: 37835022 PMCID: PMC10573672 DOI: 10.3390/jcm12196379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Perianal fistulizing Crohn's Disease (pCD) affects about 25% of patients with Crohn's Disease (CD). It remains a difficult entity to manage with a therapeutic ceiling of treatment success despite improving medical and surgical management. The refractory nature of the disease calls for an imminent need to better understand its immunopathogenesis and classification to better streamline our treatment options. In this article, we overview the current state of pCD management and discuss where the future of its management may lie.
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Affiliation(s)
- Sulak Anandabaskaran
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, UK
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Faculty of Medicine, St Vincent’s Clinical School, University of New South Wales, 390 Victoria Street, Darlinghurst, NSW 2010, Australia
| | - Luke Hanna
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, UK
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
| | - Nusrat Iqbal
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Department of Surgery and Cancer, South Kensington Campus, Imperial College London, London SW7 2BX, UK
| | - Laura Constable
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, UK
| | - Phil Tozer
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Department of Surgery and Cancer, South Kensington Campus, Imperial College London, London SW7 2BX, UK
| | - Ailsa Hart
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Department of Surgery and Cancer, South Kensington Campus, Imperial College London, London SW7 2BX, UK
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McGregor CGC, Tandon R, Simmons A. Pathogenesis of Fistulating Crohn's Disease: A Review. Cell Mol Gastroenterol Hepatol 2022; 15:1-11. [PMID: 36184031 PMCID: PMC9667304 DOI: 10.1016/j.jcmgh.2022.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 12/10/2022]
Abstract
Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.
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Affiliation(s)
- Colleen Georgette Chantelle McGregor
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Ruchi Tandon
- Pathology, Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Alison Simmons
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
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Khan MR, Ulrich JA, Hull NC, Inoue A, Harmsen WS, Faubion WA, Fletcher JG, Absah I. Perianal magnetic resonance imaging findings and their potential impact on outcome in children with perianal fistulizing Crohn disease. Pediatr Radiol 2021; 51:2481-2491. [PMID: 34490496 DOI: 10.1007/s00247-021-05158-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/25/2021] [Accepted: 07/20/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Children with perianal fistulizing Crohn disease require intensive medical management but also have a higher risk for subsequent surgical interventions. OBJECTIVE We performed a retrospective study to identify patient factors and perianal anatomical features by pelvic MR that are associated with surgical interventions in these children. MATERIALS AND METHODS We included children with Crohn disease and perianal fistula who underwent pelvic MR with available, archived images and collected demographic, clinical and laboratory data. Radiologists reviewed pelvic MR exams and identified Park classification and additional anatomical features of perianal fistulas, including fistula branching, horseshoe ramifications, abscess, inflammatory mass, supralevator extension, anal sphincter damage, proctitis and posterior anal space involvement. We performed univariate and subsequent multivariate analysis to determine features associated with subsequent surgical intervention. RESULTS Ninety-nine children with Crohn disease underwent pelvic MR. In this cohort, 69 children had no surgical interventions prior to baseline MRI, with subsequent median clinical follow-up of 5.5 years. Univariate analysis demonstrated that branching (P=0.009), supralevator extension (P=0.015) and anal sphincter damage (P=0.031) were significantly associated with subsequent surgical intervention. Age at baseline MRI was also associated with intervention (hazard ratio [HR] every 5 years: 2.13; 95% confidence interval [CI]: 1.18-3.83; P=0.012). A multivariable model identified only fistula branching (HR: 2.31; 95% CI: 1.28-4.15; P=0.005) and age (HR: 5.18; CI: 1.57-17.14; P=0.007) as independent predictors of subsequent surgery. No demographic, clinical or laboratory parameter predicted subsequent surgical intervention. CONCLUSION Age and anatomical MR features indicating fistula complexity (branching, supralevator extension) and sphincter damage confer a higher risk of subsequent surgical intervention in children with perianal Crohn disease.
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Affiliation(s)
- Muhammad Rehan Khan
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Illinois College of Medicine at Peoria, Children's Hospital of Illinois, 530 NE Glen Oak Ave., Peoria, IL, 61637, USA. .,Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
| | | | - Nathan C Hull
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Akitoshi Inoue
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - William S Harmsen
- Department of Biomedical Statistics and informatics, Mayo Clinic, Rochester, MN, USA
| | - William A Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Imad Absah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.,Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Pernat Drobež C, Ferkolj I, Potočnik U, Repnik K. Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype. Genet Test Mol Biomarkers 2018; 22:143-151. [PMID: 29446656 DOI: 10.1089/gtmb.2017.0210] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. METHODS Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. RESULTS Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. CONCLUSIONS The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.
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Affiliation(s)
- Cvetka Pernat Drobež
- 1 Department of Gastroenterology, University Medical Centre Maribor , Maribor, Slovenia
| | - Ivan Ferkolj
- 2 Department of Gastroenterology, Division of Internal Medicine, University Medical Centre Ljubljana , Ljubljana, Slovenia
| | - Uroš Potočnik
- 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,4 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
| | - Katja Repnik
- 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,4 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
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Abstract
Fistulas still represent one of the most important complications in patients with Crohn’s disease (CD). At least one third of CD patients suffer from fistulas during their disease course and amongst them longstanding remission of complex fistulas occurs only in about one third. So far, fistula pathogenesis is only partially understood. From a histopathological view, a fistula is a tube covered by flat epithelial cells. Current research suggests that the driving force for fistula development is epithelial-to-mesenchymal transition (EMT). Around the fistula, high levels of tumor necrosis factor (TNF), IL-13, and TGFβ can be detected and recent studies indicated an involvement of the intestinal microbiota. Fistula diagnosis requires clinical and surgical assessment, radiologic investigations, e.g., magnet resonance imaging and endoscopy. Routine medical treatment of fistulas includes antibiotics, immunosuppressives, and anti-TNF antibodies. There is no well-established role for calcineurin inhibitors in fistula treatment, corticosteroids appear to be even contra-productive. A promising novel approach might be the application of adipose tissue-derived or bone marrow-derived mesenchymal stem cells that have been studied recently. Due to insufficient efficacy of medical treatment and recurrence of fistulas, surgical interventions are frequently necessary. Further research is needed to better understand fistula pathogenesis aiming to develop novel treatment option for our patients.
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Sheedy SP, Bruining DH, Dozois EJ, Faubion WA, Fletcher JG. MR Imaging of Perianal Crohn Disease. Radiology 2017; 282:628-645. [PMID: 28218881 DOI: 10.1148/radiol.2016151491] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pelvic magnetic resonance (MR) imaging is currently the standard for imaging perianal Crohn disease. Perianal fistulas are a leading cause of patient morbidity because closure often requires multimodality treatments over a prolonged period of time. This review summarizes clinically relevant anal sphincter anatomy, imaging methods, classification systems, and treatment objectives. In addition, the MR appearance of healing perianal fistulas and fistula complications is described. Difficult imaging tasks including the assessment of rectovaginal fistulas and ileoanal anastomoses are highlighted, along with illustrative cases. Emerging innovative treatments for perianal Crohn disease are now available and have the promise to better control sepsis and maintain fecal continence. Different treatment modalities are selected based on fistula anatomy, patient factors, and management goals (closure versus sepsis control). Radiologists can help maximize patient care by being familiar with MR imaging features of perianal Crohn disease and knowledgeable about what features may influence therapy decisions. © RSNA, 2017 Online supplemental material is available for this article.
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Affiliation(s)
- Shannon P Sheedy
- From the Departments of Radiology (S.P.S., J.G.F.), Internal Medicine (D.H.B., W.A.F.), and Surgery (E.J.D.), Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - David H Bruining
- From the Departments of Radiology (S.P.S., J.G.F.), Internal Medicine (D.H.B., W.A.F.), and Surgery (E.J.D.), Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - Eric J Dozois
- From the Departments of Radiology (S.P.S., J.G.F.), Internal Medicine (D.H.B., W.A.F.), and Surgery (E.J.D.), Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - William A Faubion
- From the Departments of Radiology (S.P.S., J.G.F.), Internal Medicine (D.H.B., W.A.F.), and Surgery (E.J.D.), Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - Joel G Fletcher
- From the Departments of Radiology (S.P.S., J.G.F.), Internal Medicine (D.H.B., W.A.F.), and Surgery (E.J.D.), Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Lightner AL, Pemberton JH, Dozois EJ, Larson DW, Cima RR, Mathis KL, Pardi DS, Andrew RE, Koltun WA, Sagar P, Hahnloser D. The surgical management of inflammatory bowel disease. Curr Probl Surg 2017; 54:172-250. [PMID: 28576304 DOI: 10.1067/j.cpsurg.2017.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Amy L Lightner
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN.
| | - John H Pemberton
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Eric J Dozois
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - David W Larson
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Robert R Cima
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Kellie L Mathis
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Rachel E Andrew
- Division of Colorectal Surgery, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA
| | - Walter A Koltun
- Division of Colorectal Surgery, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA
| | - Peter Sagar
- Division of Colorecal surgery, St. James University Hospital, Leeds, England
| | - Dieter Hahnloser
- Division of Colorecal surgery, Lausanne University Hospital, Lausanne, Switzerland
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Sahn B, Markowitz J. The Natural History of Crohn Disease in Children. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2017:87-94. [DOI: 10.1007/978-3-319-49215-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jung ES, Park HJ, Kong KA, Choi JH, Cheon JH. Association study between OCTN1 functional haplotypes and Crohn's disease in a Korean population. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2017; 21:11-17. [PMID: 28066136 PMCID: PMC5214902 DOI: 10.4196/kjpp.2017.21.1.11] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 06/10/2016] [Accepted: 07/14/2016] [Indexed: 12/19/2022]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with multifactorial causes including environmental and genetic factors. Several studies have demonstrated that the organic cation/carnitine transporter 1 (OCTN1) non-synonymous variant L503F is associated with susceptibility to CD. However, it was reported that L503F is absent in Asian populations. Previously, we identified and functionally characterized genetic variants of the OCTN1 promoter region in Koreans. In that study, four variants demonstrated significant changes in promoter activity. In the present study, we determined whether four functional variants of the OCTN1 promoter play a role in the susceptibility to or clinical course of CD in Koreans. To examine it, the frequencies of the four variants of the OCTN1 promoter were determined by genotyping using DNA samples from 194 patients with CD and 287 healthy controls. Then, associations between genetic variants and the susceptibility to CD or clinical course of CD were evaluated. We found that susceptibility to CD was not associated with OCTN1 functional promoter variants or haplotypes showing altered promoter activities in in vitro assays. However, OCTN1 functional promoter haplotypes showing decreased promoter activities were significantly associated with a penetrating behavior in CD patients (HR=2.428, p=0.009). Our results suggest that the OCTN1 functional promoter haplotypes can influence the CD phenotype, although these might not be associated with susceptibility to this disease.
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Affiliation(s)
- Eun Suk Jung
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hyo Jin Park
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 07985, Korea
| | - Kyoung Ae Kong
- Clinical Trial Center, Ewha Womans University Medical Center, Seoul 07985, Korea
| | - Ji Ha Choi
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 07985, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
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13
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Li Y, Chen P, Sun J, Huang J, Tie H, Li L, Li H, Ren G. Meta-analysis of associations between DLG5 R30Q and P1371Q polymorphisms and susceptibility to inflammatory bowel disease. Sci Rep 2016; 6:33550. [PMID: 27633114 PMCID: PMC5025715 DOI: 10.1038/srep33550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/30/2016] [Indexed: 01/01/2023] Open
Abstract
Growing evidence from recent studies has demonstrated an association between inflammatory bowel disease (IBD) susceptibility and two polymorphisms of DLG5 R30Q (rs1248696) and P1371Q (rs2289310), but the results remain controversial. We conducted a meta-analysis including a total of 22 studies with 10,878 IBD patients and 7917 healthy controls for R30Q and 5277 IBD cases and 4367 controls for P1371Q in order to systematically assess their association with the disease. The results indicated that R30Q was significantly associated with reduced susceptibility to IBD in Europeans by allelic and dominant comparisons, but not in overall population. No significant association was found between R30Q and Crohn's disease (CD) or ulcerative colitis (UC). P1371Q was associated with increased risk of IBD in Europeans and Americans. On the contrary, a decreased risk of IBD was observed in Asian population for P1371Q. In disease subgroup analysis, we found that P1371Q was also significantly associated with CD, but this relationship was not present for UC. In conclusion, our results strongly suggest that the both polymorphisms of DLG5 are correlated with IBD susceptibility in an ethnic-specific manner. Additional well-designed studies with large and diverse cohorts are needed to further strengthen our findings.
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Affiliation(s)
- Yunhai Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Chen
- Department of Rheumatology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Jiazheng Sun
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Huang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongtao Tie
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liangliang Li
- Department of Rheumatology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Hongzhong Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Combined Medical and Surgical Approach Improves Healing of Septic Perianal Crohn's Disease. J Am Coll Surg 2016; 223:506-514.e1. [DOI: 10.1016/j.jamcollsurg.2016.05.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 05/18/2016] [Accepted: 05/23/2016] [Indexed: 12/16/2022]
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Siegmund B, Feakins RM, Barmias G, Ludvig JC, Teixeira FV, Rogler G, Scharl M. Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease. J Crohns Colitis 2016; 10:377-386. [PMID: 26681764 PMCID: PMC4946764 DOI: 10.1093/ecco-jcc/jjv228] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 12/08/2015] [Indexed: 12/19/2022]
Abstract
The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas to the disease course of patients with Crohn's disease (CD). The objectives were to reach a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas; to identify future topics in fistula research that could provide insights into pathogenesis; to develop novel therapeutic approaches; and to review current therapeutic strategies (with clarification of existing approaches to prevention, diagnosis and treatment). The results of the workshop are presented in two separate manuscripts. This manuscript describes current state-of-the-art knowledge about fistula pathogenesis, including the roles of epithelial-to-mesenchymal transition and cytokine matrix remodelling enzymes, and highlights the common association between fistulas and stenosis in CD. The review also considers the possible roles that genetic predisposition and intestinal microbiota play in fistula development. Finally, it proposes future directions and needs for fistula research that might substantially increase our understanding of this complex condition and help unravel novel therapeutic strategies and specific targets for treatment. Overall, it aims to highlight unanswered questions in fistula research and to provide a framework for future research work.
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Affiliation(s)
- Britta Siegmund
- Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Roger M Feakins
- Department of Histopathology, Royal London Hospital, London, UK
| | - Giorgos Barmias
- Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Juliano Coelho Ludvig
- ESADI Clinic and Gastroenterology Unit, Santa Isabel Hospital, Blumenau, Santa Catarina, Brazil
| | - Fabio Vieira Teixeira
- Colorectal Unit, Gastrosaude Clinic, Marilia, Sao Paulo, Brazil Department of Surgery, UNESP Botucatu, Sao Paulo, Brazil
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Park HJ, Jung ES, Kong KA, Park EM, Cheon JH, Choi JH. Identification of OCTN2 variants and their association with phenotypes of Crohn's disease in a Korean population. Sci Rep 2016; 6:22887. [PMID: 26965072 PMCID: PMC4786794 DOI: 10.1038/srep22887] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/23/2016] [Indexed: 12/19/2022] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory bowel disease and a genetic variant in the OCTN2, g.-207G > C is significantly associated with CD susceptibility. This study was aimed to identify novel OCTN2 functional promoter variants and their roles in transcriptional regulation using various in vitro assays. In addition, we investigated the association between OCTN2 genotypes and CD through genetic analysis using DNA samples from 193 patients with CD and 281 healthy controls. Among the three major promoter haplotypes of OCTN2 identified, one haplotype, H3, showed a significant decrease in promoter activity: two polymorphisms in H3 were associated with a significant reduction in promoter activity. In particular, we found that the reduced transcriptional activity of those two polymorphisms results from a reduction in the binding affinity of the activators, NF-E2 and YY1, to the OCTN2 promoter. The functional haplotype of the OCTN2 promoter was associated with clinical course of CD such as the disease behavior and need for surgery. However, genetic variants or haplotypes of OCTN2 did not affect the susceptibility to CD. Our results suggest that a common promoter haplotype of OCTN2 regulates the transcriptional rate of OCTN2 and influences the clinical course of CD.
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Affiliation(s)
- Hyo Jin Park
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, 07985, Korea
| | - Eun Suk Jung
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Korea.,Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Kyoung Ae Kong
- Clinical Trial Center, Ewha Womans University Medical Center, Seoul, 07985, Korea
| | - Eun-Mi Park
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, 07985, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Ji Ha Choi
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, 07985, Korea
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Baillie CT, Smith JA. Surgical strategies in paediatric inflammatory bowel disease. World J Gastroenterol 2015; 21:6101-16. [PMID: 26034347 PMCID: PMC4445089 DOI: 10.3748/wjg.v21.i20.6101] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/30/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) comprises two distinct but related chronic relapsing inflammatory conditions affecting different parts of the gastrointestinal tract. Crohn's disease is characterised by a patchy transmural inflammation affecting both small and large bowel segments with several distinct phenotypic presentations. Ulcerative colitis classically presents as mucosal inflammation of the rectosigmoid (distal colitis), variably extending in a contiguous manner more proximally through the colon but not beyond the caecum (pancolitis). This article highlights aspects of the presentation, diagnosis, and management of IBD that have relevance for paediatric practice with particular emphasis on surgical considerations. Since 25% of IBD cases present in childhood or teenage years, the unique considerations and challenges of paediatric management should be widely appreciated. Conversely, we argue that the organizational separation of the paediatric and adult healthcare worlds has often resulted in late adoption of new approaches particularly in paediatric surgical practice.
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Abstract
BACKGROUND While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose the appropriate therapeutic strategy for the individual patient based on the risk/benefit ratio. The aim of this review is to focus on the tools assisting the clinician in routine practice regarding the prediction of disease evolution. METHODS A literature review was performed, which was mainly based on PubMed search, using the following terms: Crohn's disease, ulcerative colitis, inflammatory bowel disease, genetics, serology, biomarkers, endoscopy, C-reactive protein, faecal calprotectin, disease evolution and complications. RESULTS For the prediction of disease evolution, clinical characteristics, particularly disease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including genetic, serological and inflammatory markers, as well as characteristics of endoscopic lesions may have an added value. CONCLUSIONS Simple clinical, biological and endoscopic tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and prospective evaluation of new genetic and biological markers are needed.
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Affiliation(s)
- Jose-Manuel Benitez
- Department of Gastroenterology, CHU Liège, and GIGA Research, Liège University, Liège, Belgium
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19
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Improving the outcome of fistulising Crohn's disease. Best Pract Res Clin Gastroenterol 2014; 28:505-18. [PMID: 24913389 DOI: 10.1016/j.bpg.2014.04.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 03/13/2014] [Accepted: 04/13/2014] [Indexed: 01/31/2023]
Abstract
Fistulas are a frequent manifestation of Crohn's disease (CD) and can result in considerable morbidity. Approximately 35% of all patients with CD will experience one fistula episode during their disease course of which 54% is perianal. The major symptoms of patients with perianal fistulas are constant anal pain, the formation of painful swellings around the anus and continuous discharge of pus and/or blood from the external fistula opening. The exact aetiology of perianal fistulas in CD patients remains unclear, but it is thought that a penetrating ulcer in the rectal mucosa caused by active CD forms an abnormal passage between the epithelial lining of the rectum and the perianal skin. Genetic, microbiological and immunological factors seem to play important roles in this process. Although the incidence of perianal fistulas in patients with CD is quite high, an effective treatment is not yet discovered. In this review all available medical and surgical therapies are discussed and new treatment options and research targets will be highlighted.
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20
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Diagnosis and treatment of perianal Crohn disease: NASPGHAN clinical report and consensus statement. J Pediatr Gastroenterol Nutr 2013; 57:401-12. [PMID: 23974063 DOI: 10.1097/mpg.0b013e3182a025ee] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes both Crohn disease (CD) and ulcerative colitis. Abdominal pain, rectal bleeding, diarrhea, and weight loss characterize both CD and ulcerative colitis. The incidence of IBD in the United States is 70 to 150 cases per 100,000 individuals and, as with other autoimmune diseases, is on the rise. CD can affect any part of the gastrointestinal tract from the mouth to the anus and frequently will include perianal disease. The first description connecting regional enteritis with perianal disease was by Bissell et al in 1934, and since that time perianal disease has become a recognized entity and an important consideration in the diagnosis and treatment of CD. Perianal Crohn disease (PCD) is defined as inflammation at or near the anus, including tags, fissures, fistulae, abscesses, or stenosis. The symptoms of PCD include pain, itching, bleeding, purulent discharge, and incontinence of stool. In this report, we review and discuss the etiology, diagnosis, evaluation, and treatment of PCD.
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Kabakchiev B, Silverberg MS. Expression quantitative trait loci analysis identifies associations between genotype and gene expression in human intestine. Gastroenterology 2013; 144:1488-96, 1496.e1-3. [PMID: 23474282 PMCID: PMC3775712 DOI: 10.1053/j.gastro.2013.03.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 01/30/2013] [Accepted: 03/01/2013] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Genome-wide association studies have greatly increased our understanding of intestinal disease. However, little is known about how genetic variations result in phenotypic changes. Some polymorphisms have been shown to modulate quantifiable phenotypic traits; these are called quantitative trait loci. Quantitative trait loci that affect levels of gene expression are called expression quantitative trait loci (eQTL), which can provide insight into the biological relevance of data from genome-wide association studies. We performed a comprehensive eQTL scan of intestinal tissue. METHODS Total RNA was extracted from ileal biopsy specimens and genomic DNA was obtained from whole-blood samples from the same cohort of individuals. Cis- and trans-eQTL analyses were performed using a custom software pipeline for samples from 173 subjects. The analyses determined the expression levels of 19,047 unique autosomal genes listed in the US National Center for Biotechnology Information database and more than 580,000 variants from the Single Nucleotide Polymorphism database. RESULTS The presence of more than 15,000 cis- and trans-eQTL was detected with statistical significance. eQTL associated with the same expression trait were in high linkage disequilibrium. Comparative analysis with previous eQTL studies showed that 30% to 40% of genes identified as eQTL in monocytes, liver tissue, lymphoblastoid cell lines, T cells, and fibroblasts are also eQTL in ileal tissue. Conversely, most of the significant eQTL have not been previously identified and could be tissue specific. These are involved in many cell functions, including division and antigen processing and presentation. Our analysis confirmed that previously published cis-eQTL are single nucleotide polymorphisms associated with inflammatory bowel disease: rs2298428/UBE2L3, rs1050152/SLC22A4, and SLC22A5. We identified many new associations between inflammatory bowel disease susceptibility loci and gene expression. CONCLUSIONS eQTL analysis of intestinal tissue supports findings that some eQTL remain stable across cell types, whereas others are specific to the sampled location. Our findings confirm and expand the number of known genotypes associated with expression and could help elucidate mechanisms of intestinal disease.
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Affiliation(s)
- Boyko Kabakchiev
- Zane Cohen Centre for Digestive Diseases, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
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Abstract
BACKGROUND Anal complications of Crohn's disease range from painless skin tags to debilitating fistulas that are imperfectly treated with tumor necrosis factor antagonists. The recent discovery of more than 190 single-nucleotide polymorphisms associated with Crohn's disease offers the opportunity to genetically define the severity of anal disease in Crohn's disease and possibly predict prognosis and anti-tumor necrosis factor response. OBJECTIVES This study aimed to identify single nucleotide polymorphisms associated with anal disease generally, septic anal disease specifically and the responsivity to anti-tumor necrosis factor treatment. DESIGN All patients with ileocolonic Crohn's disease were identified from our IBD registry. One hundred ninety-six Crohn's disease-related single-nucleotide polymorphisms were analyzed by the use of a custom microarray chip. Patients' response to anti-tumor necrosis factor treatment was then assessed. RESULTS One hundred sixteen patients with ileocolonic Crohn's disease were identified and assigned to septic anal disease (abscesses/fistulas, n = 35), benign anal disease (skin tags/fissures/isolated pain, n = 17), and no anal disease (n = 64) cohorts. Single-nucleotide polymorphism rs212388 negatively correlated with the presence of anal disease overall and septic disease specifically. The presence of the non-wild-type allele 'G' was protective of anal sepsis with homo- and heterozygotes having a 75% chance of no anal disease (p = 0.0001). The homozygous wild-type group had the highest risk of septic disease and included 3 of 4 patients requiring diverting ileostomies. Twenty-four patients were treated with anti-tumor necrosis factors. Nine had a beneficial response (assessed at >6 months); however, no single-nucleotide polymorphism correlated with anti-tumor necrosis factor response. Rs212388 is associated with the TAGAP molecule involved in T-cell activation. CONCLUSIONS Rs212388 most significantly correlated with the presence and severity of anal disease in ileocolonic Crohn's disease. A single copy of the risk allele was protective, whereas wild-type homozygotes had the highest risk of septic disease and stoma creation. In this select group, no single-nucleotide polymorphism was predictive of anti-tumor necrosis factor response. Mutations in TAGAP may predict a more benign form and course of anal disease in Crohn's disease.
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Savoye G, Salleron J, Gower-Rousseau C, Dupas JL, Vernier-Massouille G, Fumery M, Merle V, Lerebours E, Cortot A, Turck D, Salomez JL, Lemann M, Colombel JF, Duhamel A. Clinical predictors at diagnosis of disabling pediatric Crohn's disease. Inflamm Bowel Dis 2012; 18:2072-8. [PMID: 22294515 DOI: 10.1002/ibd.22898] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 01/03/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Identification of children with Crohn's disease (CD) at high risk of disabling disease would be invaluable in guiding initial therapy. Our study aimed to identify predictors at diagnosis of a subsequent disabling course in a population-based cohort of patients with pediatric-onset CD. METHODS Among 537 patients with pediatric CD diagnosed at <17 years of age, 309 (57%) with 5-year follow-up were included. Clinical and demographic factors associated with subsequent disabling CD were studied. Three definitions of disabling CD were used: Saint-Antoine and Liège Hospitals' definitions and a new pediatric definition based on the presence at maximal follow-up of: 1) growth delay defined by body mass index (BMI), weight or height lower than -2 SD Z score; and 2) at least one intestinal resection or two anal interventions. Predictors were determined using multivariate analyses and their accuracy using the kappa method considering a relevant value ≥ 0.6. RESULTS According to the Saint-Antoine definition, the rate of disabling CD was 77% and predictors were complicated behavior and L1 location. According to the Liège definition, the rate was 37% and predictors included behavior, upper gastrointestinal disease, and extraintestinal manifestations. According to the pediatric definition, the rate of disabling CD was 15%, and predictors included complicated behavior, age <14, and growth delay at diagnosis. Kappa values for each combination of predictors were, respectively, 0.2, 0.3, and 0.2 and were nonrelevant. CONCLUSIONS Clinical parameters at diagnosis are insufficient to predict a disabling course of pediatric CD. More complex models including serological and genetic biomarkers should be tested.
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Affiliation(s)
- Guillaume Savoye
- Gastroenterology Unit, EPIMAD Registry, Rouen University and Hospital, France
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Connelly TM, Koltun WA. The Role of Genetics in the Surgical Management of Inflammatory Bowel Disease. SEMINARS IN COLON AND RECTAL SURGERY 2012. [DOI: 10.1053/j.scrs.2012.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Clinical and genetic risk factors for perianal Crohn's disease in a population-based cohort. Am J Gastroenterol 2012; 107:589-96. [PMID: 22158027 DOI: 10.1038/ajg.2011.437] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Perianal Crohn's disease (CD) affects around one-quarter of CD patients and represents a distinct disease phenotype. The objective of this study was to investigate a large population-based cohort of inflammatory bowel disease (IBD) patients to identify clinical and genetic risk factors for perianal CD. METHODS Data were collected in the Canterbury IBD database, estimated to include 91% of all patients with IBD in Canterbury, New Zealand. Genotyping was performed for selected loci previously demonstrated to be associated with CD. Patients with perianal disease were then compared with both CD patients without perianal disease and healthy controls to assess the presence of potential phenotypic, environmental, and genetic risk factors. RESULTS Of the 715 CD patients in the database, 190 (26.5%) had perianal disease. In all, 507 patients with genotype data available were analyzed. Perianal disease was associated with younger age at diagnosis (P < 0.0001), complicated intestinal disease (P < 0.0001), and ileal disease location (P = 0.002). There was no association with gender, ethnicity, smoking, or breast feeding. Genotype analysis revealed an association with the neutrophil cytosolic factor 4 (NCF4) gene compared with both non-perianal CD patients (odds ratio (OR): 1.47; 95% confidence interval (CI): 1.08-1.99) and healthy controls (OR: 1.47; 95% CI: 1.10-1.95). There was no association identified with other genes, including IBD5 (OR: 0.91; 95% CI: 0.69-1.20), tumor necrosis factor α (OR: 1.04; 95% CI: 0.56-1.85), and IRGM (immunity-related guanosine triphosphatase protein type M) (OR: 1.21; 95% CI: 0.80-1.82). CONCLUSIONS This study suggests that younger age at diagnosis, complicated disease behavior, and ileal disease location are risk factors for perianal CD. In addition, this paper represents the first report of an association of the NCF4 gene with perianal disease.
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Ng SC, Woodrow S, Patel N, Subhani J, Harbord M. Role of genetic and environmental factors in British twins with inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:725-36. [PMID: 21557397 DOI: 10.1002/ibd.21747] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 03/28/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Twin studies provide insight into the complex interaction between genetic and environmental factors in the development of inflammatory bowel disease (IBD). We assessed associations between childhood environmental factors and development of Crohn's disease (CD) and ulcerative colitis (UC) in twins. METHODS Questionnaires on clinical demographics and exposure to environmental factors were sent to twins with IBD, their healthy co-twins, and their doctors. Kappa statistics were used to examine agreement between twin pairs and odds ratios were calculated by conditional logistic regression. RESULTS In all, 250 IBD twin pairs (122 CD; 125 UC; 3 CD/UC; 28 concordant pairs) were analyzed. Concordant monozygotic twins with CD showed good agreement for disease location (κ 0.88; 95% confidence interval [CI]: 0.45-1.00), disease behavior (κ 1.00; 95% CI: 0.43-1.00), and moderate agreement for age at diagnosis and need for medical and surgical therapy. Concordant monozygotic twins with UC showed good agreement for disease extent (κ 0.60; CI 0.13-1.00) and use of thiopurines (κ 0.73; CI 0.10-1.00). In discordant twins, symptomatic childhood mumps infection (odds ratio [OR], 3.8; 95% CI, 1.2-11.3) and oral contraceptives (OR, 4.0; 1.1-14.2) were associated with CD. Smoking was associated with CD (OR, 4.3; 95% CI, 1.9-9.8) but inversely associated with UC (OR, 0.3; 95% CI, 0.1-0.9). Both CD and UC twins had suffered more "gastroenteritis" and spent more time with animals than their co-twins. CONCLUSIONS Disease phenotype in CD and disease extent in UC appeared to be genetically influenced. Smoking is a risk factor for CD but is protective for UC. Early exposure to "infections" during childhood may be associated with the development of IBD.
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Affiliation(s)
- Siew C Ng
- Gastroenterology Department, Chelsea and Westminster Hospital, London, UK
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2012; 18:105-18. [PMID: 22253516 PMCID: PMC3257437 DOI: 10.3748/wjg.v18.i2.105] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 04/25/2011] [Accepted: 05/02/2011] [Indexed: 02/06/2023] Open
Abstract
Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Xuan C, Zhang BB, Yang T, Deng KF, Li M, Tian RJ. Association between OCTN1/2 gene polymorphisms (1672C-T, 207G-C) and susceptibility of Crohn's disease: a meta-analysis. Int J Colorectal Dis 2012; 27:11-9. [PMID: 21706137 DOI: 10.1007/s00384-011-1265-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE Although a number of genetic studies have attempted to link organic cation transporter 1/2 (OCTN1/2) polymorphisms to susceptibility of Crohn's disease (CD), the results were often inconsistent. The present study aimed at investigating the associations. METHODS The PubMed, EBSCO, and BIOSIS databases were searched to identify eligible studies which were published in English before April 2011. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). RESULTS A total of 15 case-control studies, containing 4,489 cases/5,351 controls for OCTN1 and 4,474 cases/5,377 controls for OCTN2 were included. Overall, significant associations were found between OCTN1/2 polymorphisms and susceptibility of Crohn's disease for all genetic models. In the subgroup analyses, significant associations were found in the Caucasian population for OCTN1 (TT vs. CC: OR = 1.425, 95% CI 1.247-1.628; TT vs. CT: OR = 1.299, 95% CI 1.149-1.468; dominant model: OR = 1.344, 95% CI 1.197-1.508; and recessive model: OR = 1.179, 95% CI 1.066-1.305) and for OCTN2 (CC vs. GG: OR = 1.309, 95% CI 1.078-1.588; CC vs. CG: OR = 1.200, 95% CI 1.002-1.438; dominant model (OR = 1.231, 95% CI 1.036-1.462; recessive model: OR = 1.148, 95% CI 1.031-1.279). Significant associations were not found in the East Asian population. CONCLUSIONS This meta-analysis suggests that OCTN1/2 polymorphisms were associated with susceptibility of CD in the Caucasian population but not in the East Asian population.
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Affiliation(s)
- Chao Xuan
- Medical College of NanKai University, No.94, the Weijin Road, Tianjin, 300071, People's Republic of China.
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2011; 17:5246-59. [PMID: 22219593 PMCID: PMC3247688 DOI: 10.3748/wjg.v17.i48.5246] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Considering the epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have so far been related to the diagnosis of Crohn's disease. These genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the strongest and most replicated associations with Crohn's disease have been demonstrated with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in the prognosis of Crohn's disease and many attempts have been made for classification of genetic profiles in Crohn's disease. CARD15 seems to be not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding of Crohn's disease genetics is of value, but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Prediction of disease complication occurrence in Crohn's disease using phenotype and genotype parameters at diagnosis. J Crohns Colitis 2011; 5:592-7. [PMID: 22115380 DOI: 10.1016/j.crohns.2011.06.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2011] [Revised: 04/07/2011] [Accepted: 06/04/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Complications associated with Crohn's disease (CD) are common and influence treatment decisions and outcomes. Appropriate early treatment may offer a therapeutic advantage to patients. The aim of our study was to indentify predictive factors for occurrence of complications at the time of CD diagnosis. METHODS The study population consisted of 269 CD patients treated during a ten year period. Risk factors compared between complicated and non-complicated disease included phenotypical characteristics, disease classification and the presence of NOD2/CARD15 mutations and single nucleotide polymorphisms in selected autophagy and phagosome genes. RESULTS Complete data was obtained for 146 patients with an average follow up of 12years. Sixty five patients (44%) developed a complication during follow up. The only independent risk factors associated with developing a complication were smoking and male gender. There was no association between developing complications and the presence of selected SNPs (P=0.07 for Tyrosine residue on both alleles in NCF4 SNP rs4821544 and P=0.06 for a Guanine residue on both alleles in ATG16L SNP rs2241880). Multivariate analysis using a backwards logistic regression model left only male gender as an independent statistically significant association with complicated disease (OR 2.6017, 95% CI: 1.17 to 5.75). The median time to developing a complication was 4years, and the most common complication was the need for surgical intervention (54%). CONCLUSIONS In the present study, a risk factor for developing CD complication was male gender. Further studies are warranted to assess additional risk factors and how such findings should affect therapy.
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Chua KH, Lian LH, Kee BP, Thum CM, Lee WS, Hilmi I, Goh KL. Identification of DLG5 and SLC22A5 gene polymorphisms in Malaysian patients with Crohn's disease. J Dig Dis 2011; 12:459-466. [PMID: 22118696 DOI: 10.1111/j.1751-2980.2011.00533.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the association of DLG5 and SLC22A5 gene polymorphisms with the onset of Crohn's disease (CD) in a Malaysian cohort. METHODS Genomic DNA of 80 CD patients and 100 healthy unrelated control individuals was extracted and analyzed via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on DLG5 (4136 C/A), DLG5_e26 and SLC22A5 (-207 G/C) genetic polymorphisms. Data obtained from the study were then subjected to statistical analysis to test for risk association. RESULTS Significant associations of both DLG5 polymorphisms with the development of CD in the Malaysian patients were observed in this study. The homozygous C genotype of the DLG5 polymorphism was significantly related to CD patients (P = 0.0023, OR = 2.5320), while the homozygous A was significant in control individuals (P = 0.0224, OR = 0.4480). In DLG5_e26 polymorphisms, we found a significant distribution of the homozygous insA genotype in CD patients (P = 0.0006, OR = 2.8916), whereas the heterozygous insA/delA genotype was significant in controls (P = 0.0007, OR = 0.3487). We hypothesized that there might be a complex interaction of both alleles, which confered a protective effect against the onset of CD. However, we did not observe any significant correlation of SLC22A5 polymorphisms with this disease. CONCLUSIONS In our study, both polymorphisms in the DLG5 gene were found to be associated with CD patients in Malaysia. Therefore, these loci can be potentially used as susceptibility markers in the Malaysian population.
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Affiliation(s)
- Kek Heng Chua
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
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Hradsky O, Dusatkova P, Lenicek M, Bronsky J, Duricova D, Nevoral J, Vitek L, Lukas M, Cinek O. Two independent genetic factors responsible for the associations of the IBD5 locus with Crohn's disease in the Czech population. Inflamm Bowel Dis 2011; 17:1523-9. [PMID: 21674708 DOI: 10.1002/ibd.21532] [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] [Received: 09/03/2010] [Accepted: 09/21/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND The role of the IBD5 locus in development of Crohn's disease (CD) has not been clarified. In the Czech population we examined its genetic association using variants of the SLC22A4 (rs1050152), SLC22A5 (rs2631367), two single nucleotide polymorphisms (SNPs) shown to be associated with CD in genome-wide studies (rs6596075 and rs2188962), and four SNPs previously shown to tag the haplotype blocks 4, 7, 9, 10 of the IBD5 locus (IGR2063b_1, IGR2230a_1, IGR100Xa_1, IGR3236a_1). METHODS The genotype, phenotype, and allelic frequencies were compared between 469 unrelated patients with CD (177 pediatric-onset, 292 adult-onset) and 470 unrelated healthy controls, all Caucasians of Czech ancestry. RESULTS The most significant difference between patients and controls was found for the SNP rs6596075 (odds ratio [OR] = 0.70 for the G allele; 95% CI 0.52-0.94) in the dominant model and SNP IGR2063b_1 (OR = 1.38 for the G allele; 95% CI 1.14-1.67) in the log-additive model. We found a strong linkage disequilibrium across the IBD5 locus except rs6596075. The haplotype consisting of minor alleles of all tested SNPs except rs6596075 was carried by 31% patients and 23% control subjects (OR = 1.35, 95% CI 1.06-1.72). The association of variants in SLC22A4 and SLC22A5 was dependent on this risk haplotype, while the strong association of the rs6596075 was seemingly independent. In the analysis of subphenotypes we found only an association of the penetrating disease with rs6596075 (OR = 2.13; 95% CI 1.31-3.47). CONCLUSIONS Our study confirms the importance of IBD5 in determining CD susceptibility, and demonstrates that two independent genetic factors may be responsible for the association observed within this locus.
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Affiliation(s)
- Ondrej Hradsky
- Department of Pediatrics, University Hospital Motol and Second Faculty of Medicine, Charles University in Prague, Czech Republic.
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Fujiya M, Inaba Y, Musch MW, Hu S, Kohgo Y, Chang EB. Cytokine regulation of OCTN2 expression and activity in small and large intestine. Inflamm Bowel Dis 2011; 17:907-16. [PMID: 20722056 PMCID: PMC2990793 DOI: 10.1002/ibd.21444] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Accepted: 07/13/2010] [Indexed: 12/21/2022]
Abstract
BACKGROUND The organic cation transporter OCTN2 is located on the IBD5 risk allele and has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). OCTN2 is expressed in the apical membrane and transports many solutes including bacteria-derived mediators that may be involved in host-microbial interactions. To explore its role further, we examined potential regulatory factors in human IBD and in experimental models of OCTN2 expression. METHODS Human colonic epithelial cells (Caco2BBE) were used to investigate the effects of inflammatory mediators on OCTN2 activity and expression. Apical membrane expression of OCTN2 was assessed by surface biotinylation. Rag-1(-/-) -deficient mice were used to determine the potential role of adaptive immune cells in the regulation of OCTN2 expression. C57Bl/6 mice were treated with the cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) to determine the effects on OCTN2 expression and activity. OCTN2 expression in human IBD specimens was assessed by Western blotting and immunohistochemistry. RESULTS OCTN2 activity and expression are regulated by the state of intestinal inflammation. OCTN2 expression in colonic tissues of Rag-1(-/-) -deficient mice was reduced. Treatment with IFN-γ and TNF-α increased intestinal OCTN2 expression, particularly in the colon. IFN-γ increased both total and apical membrane expression of Caco2BBE OCTN2, whereas TNF-α stimulated apical expression. Colonic epithelial OCTN2 expression was increased in actively inflamed areas of both Crohn's disease and ulcerative colitis. CONCLUSIONS Intestinal epithelial OCTN2 expression is increased by intestinal inflammation, most likely through increased levels of proinflammatory cytokines. These findings suggest that OCTN2 may participate to restoration of intestinal homeostasis under conditions of inflammation-associated stress.
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Affiliation(s)
- Mikihiro Fujiya
- Department of Gastroenterology, Hepatology, and Life Style Diseases, Asahikawa Medical School, Asahikawa, Japan
| | - Yuhei Inaba
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago Illinois
| | - Mark W. Musch
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago Illinois
| | - Shien Hu
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago Illinois
| | - Yutaka Kohgo
- Department of Gastroenterology, Hepatology, and Life Style Diseases, Asahikawa Medical School, Asahikawa, Japan
| | - Eugene B. Chang
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago Illinois
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Wang J, Wang X, Yang H, Wu D, Wang L, Qian J. Contribution of the IBD5 locus to inflammatory bowel disease: a meta-analysis. Hum Genet 2011; 129:597-609. [PMID: 21279723 DOI: 10.1007/s00439-011-0952-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 01/17/2011] [Indexed: 12/13/2022]
Abstract
To evaluate the association of the IBD5 locus to the predisposition of inflammatory bowel diseases (IBDs), a series of meta-analyses between five IBD5 variants (OCTN1 C1672T, OCTN2 G-207C, OCTN1/2 TC haplotype, IGR2096a_1, IGR2198a_1 and IGR2230a_1) and Crohn's disease (CD) and ulcerative colitis (UC) were performed, which included a total of 26 studies. Overall, five IBD5 variants in a per-allele model of inheritance were significantly associated with elevated CD risk (for OCTN1: OR = 1.23, 95% CI = 1.16-1.30, P < 0.001; for OCTN2: OR = 1.20, 95% CI = 1.11-1.30, P < 0.001; for IGR2096a_1: OR = 1.36, 95% CI = 1.24-1.46, P < 0.001; for IGR2198a_1: OR = 1.34, 95% CI = 1.24-1.46, P < 0.001; for IGR2230a_1: OR = 1.35, 95% CI = 1.23-1.48, P < 0.001) and OCTN1/2 TC haplotype (OR = 1.32, 95% CI = 1.22-1.43, P < 0.001). In the subgroup analysis, the statistically significant associations were also observed in adult- and pediatric-onset CD and in Caucasians for five IBD5 variants and the OCTN1/2 TC haplotype. A statistically significant increase in the risk of UC was detected in a recessive model of inheritances for OCTN1 (OR = 1.23, 95% CI = 1.08-1.40, P < 0.001), OCTN2 (OR = 1.18, 95% CI = 1.05-1.33, P = 0.006), IGR2096a_1 (OR = 1.37, 95% CI = 1.15-1.62, P < 0.001) and IGR2198a_1 (OR = 1.35, 95% CI = 1.10-1.66, P = 0.004); the increased risks of UC were maintained in the adult and Caucasian subgroups, but not the pediatric subgroup. In summary, our results suggested that the IBD5 locus contributes to the susceptibility of CD in a per-allele manner in adults, children and Caucasians, and the locus contributes to the susceptibility of UC in a recessive manner in adult and Caucasian populations.
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Affiliation(s)
- Jian Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People's Republic of China
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Abstract
The intestinal barrier is one of the most dynamic surfaces of the body. It is here where a single layer of epithelial cells mediates the intricate encounters that occur between the host's immune system and a multitude of potential threats present in the intestinal lumen. Several key factors play an important role in the final outcome of this interaction, including the state of oxidative stress, the level of activation of the immune cells, and the integrity of the epithelial barrier. This chapter describes the main evidence demonstrating the impact that l-carnitine has on each of these factors. These findings, combined with the demonstrated safety profile of l-carnitine, underscore the potential therapeutic value of l-carnitine supplementation in humans suffering from intestinal inflammation and highlight the functional data supporting an association between Crohn's disease and mutations in the l-carnitine transporter genes.
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Abstract
During the course of the disease, most patients with Crohn's disease (CD) may eventually develop a stricturing or a perforating complication, and a significant number of patients with both CD and ulcerative colitis will undergo surgery. In recent years, research has focused on the determination of factors important in the prediction of disease course in inflammatory bowel diseases to improve stratification of patients, identify individual patient profiles, including clinical, laboratory and molecular markers, which hopefully will allow physicians to choose the most appropriate management in terms of therapy and intensity of follow-up. This review summarizes the available evidence on clinical, endoscopic variables and biomarkers in the prediction of short and long-term outcome in patients with inflammatory bowel diseases.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, H-1083 Budapest, Koranyi S 2A, Hungary.
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Lakatos PL, Kiss LS. Is the disease course predictable in inflammatory bowel diseases? World J Gastroenterol 2010; 16:2591-2599. [PMID: 20518079 PMCID: PMC2880770 DOI: 10.3748/wjg.v16.i21.2591] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2009] [Revised: 12/16/2009] [Accepted: 12/23/2009] [Indexed: 02/06/2023] Open
Abstract
During the course of the disease, most patients with Crohn's disease (CD) may eventually develop a stricturing or a perforating complication, and a significant number of patients with both CD and ulcerative colitis will undergo surgery. In recent years, research has focused on the determination of factors important in the prediction of disease course in inflammatory bowel diseases to improve stratification of patients, identify individual patient profiles, including clinical, laboratory and molecular markers, which hopefully will allow physicians to choose the most appropriate management in terms of therapy and intensity of follow-up. This review summarizes the available evidence on clinical, endoscopic variables and biomarkers in the prediction of short and long-term outcome in patients with inflammatory bowel diseases.
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Henckaerts L, Vlietinck R, Derom C, Boonen S, Rutgeerts P, Vermeire S. Transmission ratio distortion of DLG5 R30Q: evidence for prenatal selection? Inflamm Bowel Dis 2010; 16:910-1. [PMID: 19774648 DOI: 10.1002/ibd.21109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Lin Z, Nelson L, Franke A, Poritz L, Li TY, Wu R, Wang Y, MacNeill C, Thomas NJ, Schreiber S, Koltun WA. OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease. J Crohns Colitis 2010; 4:132-8. [PMID: 21122496 DOI: 10.1016/j.crohns.2009.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 09/07/2009] [Accepted: 09/08/2009] [Indexed: 02/07/2023]
Abstract
PURPOSE A two-allele haplotype of TC (OCTN1 rs1050152 and OCTN2 -207G→C) is associated with Crohn's disease (CD). The association has been replicated in different populations, but also failed in some studies. The present study is to replicate the association of OCTN1 rs1050152 and examine another variant rs272879 with familial and sporadic inflammatory bowel disease (IBD) in a cohort from central Pennsylvania, USA. METHODS The study samples (n=465) included 212 inflammatory bowel disease patients (CD=115, UC=97), including 103 familial (CD=55, UC=46) and 111 sporadic (CD=60, UC=51) IBD, 139 non-IBD family members from a familial IBD registry, and 114 unrelated healthy controls. A total of 12 OCTN1 variants within exonic sequences were examined. Two nonsynonymous SNPs, rs1050152 (L503F) and rs272879 (L395V) were genotyped by a PCR-based RFLP/cRFLP method and statistically analyzed. These samples with an additional 141 unrelated healthy samples were also genotyped for rs1050152 using the SNPlex™ Genotyping System. RESULTS The OCTN1 rs1050152 is associated with CD (OR=1.745, 95% CI=1.019-2.990, χ²=4.129, p=0.042) and with IBD (OR=1.68, 95% CI=1.052-2.676, χ²=4.732, p=0.030); while the variant rs272879 is not associated with IBD, CD or ulcerative colitis (UC). The distribution of the rs1050152 variant showed a high level of the T allele in male UC (OR=2.585, 95% CI=1.139-5.869, p=0.023) and IBD (OR=2.039, 95% CI=1.024-4.059, p=0.042) patients, and in female CD patients (OR=2.329, 95% CI=1.038-5.226, ρ value=0.039). CONCLUSION The present results replicated the association of the OCTN1 rs1050152 (L503F) variant with CD and IBD overall. A weak gender-specific effect of rs1050152 (L503F) on male UC and female CD was observed.
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Affiliation(s)
- Zhenwu Lin
- Department of Surgery, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
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Zhang Z, Rosenbaum JT, Zhong W, Lim C, Hinrichs DJ. Costimulation of Th17 cells: Adding fuel or putting out the fire in the inflamed gut? Semin Immunopathol 2010; 32:55-70. [PMID: 20119686 DOI: 10.1007/s00281-009-0190-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Accepted: 12/21/2009] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease, typified by Crohn's disease and ulcerative colitis, is a common disorder characterized by recurrent and serious inflammation of the gastrointestinal tract. It is well documented that T cells play a pivotal role in the development of inflammatory bowel disease. Th17 cells are a unique T cell subpopulation implicated in inflammatory bowel disease and many other autoimmune/inflammatory diseases. However, the regulatory mechanism of Th17 activation and proliferation has not been defined completely. Recent studies have shown that the ligation of several costimulatory receptor-ligand pairs contributes to the activation, differentiation, and proliferation of T lymphocytes including the Th17 subset. In this review, we will discuss the emerging evidence on the role of Th17 cells in inflammatory bowel disease pathogenesis as well as the effect of costimulatory molecules on Th17 development and consider if the need for such costimulation of T lymphocytes provides a target for the development of novel therapeutic strategy.
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Affiliation(s)
- Zili Zhang
- Department of Pediatrics, Oregon Health & Science University, Portland, 97239, USA.
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Abstract
Clinical presentation at diagnosis and disease course of both Crohn's disease (CD) and ulcerative colitis (UC) are heterogeneous and variable over time. During follow up, intestinal strictures or perforation may eventually develop at most patients with CD, and significant number of patients will undergo surgery. Much emphasis was laid in recent years on the determination of important predictive factors. Since early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. This review article summarizes the available literature on important clinical, endoscopic, fecal, serological/routine laboratory and genetic factors and hopefully will assist clinicians in the decision making of daily practice when choosing the treatment strategy for their patients with inflammatory bowel diseases.
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Affiliation(s)
- Lajos Sándor Kiss
- Semmelweis Egyetem, Altalános Orvostudományi Kar I. Belgyógyászati Klinika Budapest.
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Abstract
Technological advances in genomics and transcriptomics have resulted in the introduction of molecular tests into the clinical arena. Despite established uses of such tests in the oncology field, their integration into the management of complex diseases has not been widely evaluated. Progress in the field of inflammatory bowel disease (IBD) genetics has been rapid in recent years, and these advances have provided more urgent impetus to investigating the role of molecular tests in IBD. This article summarizes the current state of molecular testing available for IBD, and the potential utility of such tests as research in the area widens.
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Talián G, Lakner L, Bene J, Komlósi K, Horváth K, Gasztonyi B, Miheller P, Figler M, Mózsik G, Tulassay Z, Melegh B. Plasma carnitine ester profiles in Crohn's disease and ulcerative colitis patients with different IGR2230a_1 genotypes. Int J Immunogenet 2009; 36:329-335. [PMID: 19735486 DOI: 10.1111/j.1744-313x.2009.00834.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
An association has been repeatedly demonstrated between inflammatory bowel disease (IBD) and the IBD5 locus in the 5q31 chromosomal region. The aim of the present study was to examine the prevalence of the IGR2230a_1 intronic nucleotide polymorphism of the slc22a5 gene (coding for the OCTN2 carnitine transporter protein) lying within this region, and its possible relationship with the carnitine metabolism in Hungarian IBD patients and controls. We genotyped by restriction fragment length polymorphism 200 Crohn's disease (CD) and 246 ulcerative colitis (UC) patients, as well as 187 healthy controls. From plasma samples we determined detailed carnitine ester profiles of 76 CD, 43 UC patients and 45 control persons using electrospray ionization triple quadruple tandem mass spectrometry. The distribution of the genotypes was not significantly different in the CD or the UC group compared with the controls. We found no significant alterations of the carnitine profile in the carrier/non-carrier or the homozygote/non-homozygote comparisons in both the CD and the UC groups, stratified by IGR2230a_1 genotype. Our data suggest that this polymorphism alone is not associated with CD and UC in the Hungarian population, and has no effect on the carnitine metabolism.
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Affiliation(s)
- G Talián
- Department of Medical Genetics and Child Development, University of Pécs, H-7624 Pécs, Hungary
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Tozer PJ, Whelan K, Phillips RKS, Hart AL. Etiology of perianal Crohn's disease: role of genetic, microbiological, and immunological factors. Inflamm Bowel Dis 2009; 15:1591-8. [PMID: 19637358 DOI: 10.1002/ibd.21026] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Perianal fistulation is a common complication of Crohn's disease (CD). Fistulating perianal CD appears to represent a distinct phenotype of CD, separate from luminal fistulating disease, with differing disease behavior and which often requires different therapeutic strategies. The etiology of Crohn's perianal fistulae appears to have genetic, microbiological, and immunological components. Relationships with IBD5, which codes for the organic/cation transporter and IRGM, important in the autophagy pathway, have been identified but further genetic associations remain elusive. The partially efficacious use of antibiotics and fecal diversion imply a microbiological component and, similarly, the partial efficacy of immunosuppressants and anti-tumor necrosis factor alpha (TNFalpha) treatments suggest not only that an immunological process is taking place, but also that microbiota alone cannot account for the pathogenesis. Recent work implicates failures in the tissue injury/repair process with myofibroblasts, matrix metalloproteinases, and an epithelial-to-mesenchymal transition being possible culprits. We examine these areas in a review of the current understanding of the etiology of Crohn's perianal fistulae.
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Henckaerts L, Van Steen K, Verstreken I, Cleynen I, Franke A, Schreiber S, Rutgeerts P, Vermeire S. Genetic risk profiling and prediction of disease course in Crohn's disease patients. Clin Gastroenterol Hepatol 2009; 7:972-980.e2. [PMID: 19422935 DOI: 10.1016/j.cgh.2009.05.001] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Accepted: 05/01/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Clinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated. METHODS Complete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7-22). Fifty CD-associated polymorphisms were genotyped. Kaplan-Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time. RESULTS Homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60-18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13-69.78; P = .04 and OR, 0.56; 95% CI, 0.38-0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present. CONCLUSIONS CD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach.
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Affiliation(s)
- Liesbet Henckaerts
- Department of Medicine, Gastroenterology Section, Catholic University of Leuven, Leuven, Belgium.
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Lakner L, Csöngei V, Magyari L, Varga M, Miheller P, Sarlós P, Orosz P, Bári Z, Takács I, Járomi L, Sáfrány E, Sipeky C, Bene J, Tulassay Z, Döbrönte Z, Melegh B. [Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases]. Orv Hetil 2009; 150:1375-1380. [PMID: 19581171 DOI: 10.1556/oh.2009.28677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
UNLABELLED The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. PATIENTS AND METHODS Total of 440 patients, 206 with Crohn's disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. RESULTS Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn's disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn's disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn's disease (OR=1.694, 95% CI: 1.137-2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103-2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. CONCLUSIONS Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state.
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Affiliation(s)
- Lilla Lakner
- Vas Megyei Markusovszky Kórház Nonprofit Zrt. Gasztroenterológiai és Belgyógyászati Osztály Szombathely
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Lakner L, Csöngei V, Sarlós P, Járomi L, Sáfrány E, Varga M, Orosz P, Magyari L, Bene J, Miheller P, Tulassay Z, Melegh B. IGR2096a_1 T and IGR2198a_1 C alleles on IBD5 locus of chromosome 5q31 region confer risk for Crohn's disease in Hungarian patients. Int J Colorectal Dis 2009; 24:503-507. [PMID: 19214536 DOI: 10.1007/s00384-009-0670-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31. MATERIALS AND METHODS DNA of 217 Crohn's disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods. RESULTS Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn's disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn's disease (OR = 1.748, 95% CI 1.186-2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119-2.423, p = 0.011 for C allele of IGRs). CONCLUSION The data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.
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Affiliation(s)
- Lilla Lakner
- Department of Medicine and Gastroenterology, Markusovszky Hospital, Szombathely, Hungary
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Abstract
Crohn's disease and ulcerative colitis are chronic inflammatory disorders caused by a disruptive interaction between the immune system and gut luminal factors. Although the exact aetiology of IBD remains unclear, accumulating data, including genome-wide association studies (GWAS), have advanced our understanding of the immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis. It focuses on past and recent advances in our understanding of IBD, including genetics and immunobiology. Recently published GWAS have confirmed earlier findings related to the NOD2 gene and the IBD5 locus. In addition, over 30 novel loci have been identified. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal flora in the pathogenesis of inflammatory bowel disease.
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Affiliation(s)
- Casper G Noomen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, C4-12 Leiden, the Netherlands.
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Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort. Am J Gastroenterol 2009; 104:630-8. [PMID: 19174780 DOI: 10.1038/ajg.2008.112] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. METHODS We performed a large replication study in 2,731 Dutch and Belgian IBD patients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genes IL23R, ATG16L1, and NELL1, were studied. RESULTS We confirmed the associations with IL23R (rs11209026, P=2.69E-12), ATG16L1 (rs2241880, P=4.82E-07), IRGM (rs4958847, P=2.26E-05), NKX2-3 (rs10883365, P=5.91E-06), 1q24 (rs12035082, P=1.51E-05), 5p13 (rs17234657, P=2.62E-05), and 10q21 (rs10761659, P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503, P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977, P=1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD. CONCLUSIONS We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions.
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Magyari L, Melegh B. [Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients]. Orv Hetil 2009; 150:81-8. [PMID: 19103559 DOI: 10.1556/oh.2009.28445] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We examined several susceptibility genetic variants to inflammatory bowel disease (Crohn's disease, ulcerative colitis) in Hungarian population, such as the CARD15 R702W, G908R, 1007finsC genetic variants, the SLC22A4 C1672T and SLC22A5 G-207C variants and their determined TC haplotype, the CTLA4 gene A+49G genetic variant and the rs10889677 C/A, rs2201841 T/C, rs1884444 G/T variants of the IL23R gene. We examined 201 adult patients with Crohn's disease, 241 adult patients with ulcerative colitis and 19 pediatric patients with Crohn's disease. For control 235 adult and 49 pediatric subjects were used. The genotyping was carried out using PCR/RFLP methods and direct sequencing. From the CARD15 gene mutations in the adult Crohn's disease population the 1007finsC, while in the pediatric population the 1007finsC and the G908R were significantly associated with an increased risk for Crohn's disease. We found no significant differences comparing the results of the patients and the controls by the SLC22A4, SLC22A5 genetic variants and the TC haplotype. The A+49G variant of the CTLA4 gene was not an independent determinant to inflammatory bowel disease. We found that the IL23R gene variants, rs10889677 C/A and rs2201841 T/C appear to increase susceptibility to Crohn's disease. It depends on the different populations whether this genetic variant means an obligatory risk factor to inflammatory bowel disease.
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Affiliation(s)
- Lili Magyari
- Pécsi Tudományegyetem, Altalános Orvostudományi Kar, Orvosi Genetikai és Gyermekfejlodéstani Intézet, Pécs
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