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Simovic I, Hilmi I, Ng RT, Chew KS, Wong SY, Lee WS, Riordan S, Castaño-Rodríguez N. ATG16L1 rs2241880/T300A increases susceptibility to perianal Crohn's disease: An updated meta-analysis on inflammatory bowel disease risk and clinical outcomes. United European Gastroenterol J 2024; 12:103-121. [PMID: 37837511 PMCID: PMC10859713 DOI: 10.1002/ueg2.12477] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/17/2023] [Indexed: 10/16/2023] Open
Abstract
BACKGROUND ATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis. OBJECTIVES To perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features. METHODS Literature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (ORP ) and 95% CI were calculated under the random effects model. RESULTS Our analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (ORP : 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (ORP : 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (ORP : 1.21, 95% CI: 1.07-1.38, p-value: 0.003). CONCLUSIONS ATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary.
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Affiliation(s)
- Isidora Simovic
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales, Australia
| | - Ida Hilmi
- Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Ruey Terng Ng
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Kee Seang Chew
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Shin Yee Wong
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Way Seah Lee
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Stephen Riordan
- Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Kuala Lumpur, Malaysia
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2
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Sarter H, Savoye G, Marot G, Ley D, Turck D, Hugot JP, Vasseur F, Duhamel A, Wils P, Princen F, Colombel JF, Gower-Rousseau C, Fumery M. A Novel 8-Predictors Signature to Predict Complicated Disease Course in Pediatric-onset Crohn's Disease: A Population-based Study. Inflamm Bowel Dis 2023; 29:1793-1804. [PMID: 37266570 DOI: 10.1093/ibd/izad090] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Indexed: 06/03/2023]
Abstract
BACKGROUND The identification of patients at high risk of a disabling disease course would be invaluable in guiding initial therapy in Crohn's disease (CD). Our objective was to evaluate a combination of clinical, serological, and genetic factors to predict complicated disease course in pediatric-onset CD. METHODS Data for pediatric-onset CD patients, diagnosed before 17 years of age between 1988 and 2004 and followed more than 5 years, were extracted from the population-based EPIMAD registry. The main outcome was defined by the occurrence of complicated behavior (stricturing or penetrating) and/or intestinal resection within the 5 years following diagnosis. Lasso logistic regression models were used to build a predictive model based on clinical data at diagnosis, serological data (ASCA, pANCA, anti-OmpC, anti-Cbir1, anti-Fla2, anti-Flax), and 369 candidate single nucleotide polymorphisms. RESULTS In total, 156 children with an inflammatory (B1) disease at diagnosis were included. Among them, 35% (n = 54) progressed to a complicated behavior or an intestinal resection within the 5 years following diagnosis. The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination and good calibration, with an area under the curve of 0.80 after correction for optimism bias (sensitivity, 79%, specificity, 74%, positive predictive value, 61%, negative predictive value, 87%). Decision curve analysis confirmed the clinical utility of the model. CONCLUSIONS A combination of clinical, serotypic, and genotypic variables can predict disease progression in this population-based pediatric-onset CD cohort. Independent validation is needed before it can be used in clinical practice.
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Affiliation(s)
- Hélène Sarter
- Lille Hospital and University, Public Health, Epidemiology and Economic Health, EPIMAD registry, Regional house of clinical research, F-59000 Lille, France
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Guillaume Savoye
- Rouen Hospital and University, Gastroenterology Unit, EPIMAD registry, Rouen, France
| | - Guillemette Marot
- University of Lille, CHU Lille, ULR 2694-METRICS: Evaluation des Technologies de Santé et des Pratiques Médicales, F-59000 Lille, France
- Inria Lille Nord Europe, Modal, Lille, France
| | - Delphine Ley
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, F-59000 Lille, France
- Lille University Jeanne de Flandre Children's Hospital and Faculty of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Lille, France
| | - Dominique Turck
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, F-59000 Lille, France
- Lille University Jeanne de Flandre Children's Hospital and Faculty of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Lille, France
| | - Jean-Pierre Hugot
- Centre de Recherche sur l'Inflammation, UMR1149 INSERM et Université de Paris, France
- Department of Pediatric Gastroenterology, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Francis Vasseur
- University of Lille, CHU Lille, ULR 2694-METRICS: Evaluation des Technologies de Santé et des Pratiques Médicales, F-59000 Lille, France
| | - Alain Duhamel
- University of Lille, CHU Lille, ULR 2694-METRICS: Evaluation des Technologies de Santé et des Pratiques Médicales, F-59000 Lille, France
| | - Pauline Wils
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, F-59000 Lille, France
- Gastroenterology Unit, Lille Hospital and University, Lille, France
| | | | | | - Corinne Gower-Rousseau
- Lille Hospital and University, Public Health, Epidemiology and Economic Health, EPIMAD registry, Regional house of clinical research, F-59000 Lille, France
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, F-59000 Lille, France
- Research and Public Health Unit, Reims University & Hospital, Robert-Debré Hospital, Reims, France
| | - Mathurin Fumery
- Amiens Hospital and University, Gastroenterology Unit, EPIMAD Registry, and PeriTox, UMR I-01, Amiens, France
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3
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Wu PB, Zhang Y, Nie G, Huang X, Yu YJ, Yin AN, Zhou R, He CP, Wang P. Association between genetic variants in ZNF365 and inflammatory bowel disease risk in Caucasians: a meta-analysis and trial sequential analysis. Expert Rev Clin Immunol 2021; 17:915-921. [PMID: 34092165 DOI: 10.1080/1744666x.2021.1939012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE The published studies regarding the relationships between zinc finger 365 (ZNF365) polymorphisms and inflammatory bowel disease (IBD) risk in Caucasians have yielded conflicting results. Therefore, we performed a meta-analysis to clarify this issue. METHODS The Electronic databases of PubMed, Web of Science, Wiley Online Library, and EMBASE were searched for eligible studies up to 31 November 2020. The quality of eligible studies was evaluated using the Newcastle-Ottawa Scale. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) under different genetic models were calculated to assess the strength of associations. RESULTS A total of 22 relevant case-control studies with 9542 ulcerative colitis (UC) patients and 13,886 controls, as well as 13,651 Crohn's disease (CD) patients and 15,256 controls, were involved in our meta-analysis. rs10761659 polymorphism significantly decreased CD and UC risk (except for the heterozygous model and the dominant model in UC), and rs10995271 polymorphism was significantly associated with UC (except for the heterozygous model and dominant model) rather than CD. CONCLUSIONS The meta-analysis demonstrated that the rs10761659 polymorphism might be a protective factor for both UC and CD in Caucasians, while the rs10995271 polymorphism might be a risk factor for UC rather than CD in Caucasians.
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Affiliation(s)
- Peng-Bo Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei China
| | - Yu Zhang
- Infrastructure Management Department, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Gang Nie
- Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong China
| | - Xu Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei China
| | - Yuan-Jie Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei China
| | - An-Ning Yin
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei China
| | - Rui Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei China
| | - Chun-Ping He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei China
| | - Peng Wang
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
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4
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Wu PB, Qian R, Hong C, Guo YT, Yu YJ, Zhang G, Tan SY. Association between PTGER4 polymorphisms and inflammatory bowel disease risk in Caucasian: A meta-analysis. Medicine (Baltimore) 2020; 99:e19756. [PMID: 32846747 PMCID: PMC7447366 DOI: 10.1097/md.0000000000019756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The results from previous studies on association between prostaglandin E receptor 4 (PTGER4) polymorphisms and inflammatory bowel disease (IBD) risk in Caucasian were conflict. The present study aimed to investigate the genetic association by conducting a meta-analysis. METHODS Systematic literature search was conducted through Wiley Online Library, Chinese National Knowledge Infrastructure (CNKI), and PubMed databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to investigate the associations between rs4613763 T/C, 17234657T/G polymorphisms, and IBD risk in Caucasian. RESULTS Twenty case-control studies consisting of 18,495 Crohn disease (CD) patients and 4203 ulcerative colitis (UC) patients, as well as 26,063 controls were included in this meta-analysis. The rs4613763T/C polymorphism had obvious influence on CD, UC risk in Caucasian. However, rs17234657T/G polymorphism had obvious influence on CD but not UC in Caucasian. CONCLUSION This meta-analysis suggested that both the rs4613763 T/C, rs17234657T/G polymorphisms had obvious influence on risk of CD in Caucasian. In addition, rs4613763 T/C, polymorphism had obvious influence on risk of UC in Caucasian.
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Affiliation(s)
- Peng-Bo Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei
| | - Rao Qian
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei
| | - Chai Hong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei
| | - Yi-tian Guo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei
| | - Yuan-jie Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei
| | - Guo Zhang
- Department of Gastroenterology, Guangxi People Hospital, Guangxi Zhuang Autonomous Region, Nanning, China
| | - Shi-Yun Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei
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Noor NM, Verstockt B, Parkes M, Lee JC. Personalised medicine in Crohn's disease. Lancet Gastroenterol Hepatol 2020; 5:80-92. [PMID: 31818474 DOI: 10.1016/s2468-1253(19)30340-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 08/19/2019] [Accepted: 08/21/2019] [Indexed: 12/13/2022]
Abstract
Similar to many immune-mediated diseases, Crohn's disease follows a relapsing-remitting pattern, with a variable disease course and heterogeneous clinical outcomes. Frequency of flare-ups, development of complications, and response to treatment collectively determine the effect on a patient's quality of life, which can vary from minimal disruption to profound disability or death. Despite recent advances in the understanding of complex disease pathogenesis, including for Crohn's disease, management decisions are still typically made using a one-size-fits-all approach. Indeed, the inability to reliably predict clinical outcomes in a way that could guide future therapy represents a major unmet need. Recently, several important insights have been made into the biology underlying outcomes in Crohn's disease. In this Review, we will summarise these insights and discuss how greater understanding of these disease mechanisms can be used to develop clinically useful biomarkers, identify novel approaches to optimise disease control, and help deliver the goal of personalised medicine.
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Affiliation(s)
- Nurulamin M Noor
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Bram Verstockt
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Miles Parkes
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - James C Lee
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Building, Cambridge Biomedical Campus, Cambridge, UK.
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6
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O'Donnell S, Borowski K, Espin-Garcia O, Milgrom R, Kabakchiev B, Stempak J, Panikkath D, Eksteen B, Xu W, Steinhart AH, Kaplan GG, McGovern DPB, Silverberg MS. The Unsolved Link of Genetic Markers and Crohn's Disease Progression: A North American Cohort Experience. Inflamm Bowel Dis 2019; 25:1541-1549. [PMID: 30801121 DOI: 10.1093/ibd/izz016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 12/07/2018] [Accepted: 01/30/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND While progress has been made in the identification of Crohn's disease (CD) susceptibility loci, efforts to identify a genetic basis for disease progression have been less fruitful. The specific aim of this study was to build upon the major genetic advances made in IBD by applying genome-wide technologies toward predicting disease progression in CD. METHODS Crohn's disease cases (n = 1495) from 3 IBD centers were reviewed by experienced physicians. Clinical and demographic details were collected, focusing on the time to first disease progression. Genome-wide association (GWA) analysis was carried out on 3 clinical outcomes: 1) time to disease progression; 2) time to first abdominal surgery; and 3) a binary analysis of indolent vs progressive disease. Cox-proportional hazard and logistic regression models were used. RESULTS A GWA analysis was carried out to determine any genetic variation associated with the time to disease progression; 662 cases were included after quality control (QC) and exclusion of any cases with B2/B3 behavior at baseline (n = 450). There were 1360 cases included after QC in the time to abdominal surgery analysis. No variant reached genome-wide significance in any of the 3 analyses performed. Eight known IBD susceptibility single nucleotide polymorphism (SNPs) were found to be associated with time-to-abdominal surgery SMAD3 (rs17293632), CCR6 (rs1819333), CNTF (rs11229555), TSPAN14 (rs7097656), CARD9 (rs10781499), IPMK (rs2790216), IL10 (rs3024505), and SMURF1 (rs9297145) (P < 0.05). CONCLUSION Our GWA study failed to show any SNP-phenotype association reaching genome-wide significance. It is likely that multiple variables affect disease progression, with genetic factors potentially having only a small effect size.
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Affiliation(s)
- Sarah O'Donnell
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Krzysztof Borowski
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Osvaldo Espin-Garcia
- Department of Biostatistics, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Raquel Milgrom
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Boyko Kabakchiev
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Joanne Stempak
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Deepah Panikkath
- Medical Genetics Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Bertus Eksteen
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
| | - Wei Xu
- Department of Biostatistics, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - A Hillary Steinhart
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Gilaad G Kaplan
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
| | - Dermot P B McGovern
- Medical Genetics Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Mark S Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
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Lee JC. Beyond disease susceptibility-Leveraging genome-wide association studies for new insights into complex disease biology. HLA 2018; 90:329-334. [PMID: 29106067 DOI: 10.1111/tan.13170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 10/31/2017] [Indexed: 12/12/2022]
Abstract
Genetic studies in complex diseases have been highly successful, but have also been largely one-dimensional: predominantly focusing on the genetic contribution to disease susceptibility. While this is undoubtedly important-indeed it is a pre-requisite for understanding the mechanisms underlying disease development-there are many other important aspects of disease biology that have received comparatively little attention. In this review, I will discuss how existing genetic data can be leveraged to provide new insights into other aspects of disease biology, why such insights could change the way we think about complex disease, and how this could provide opportunities for better therapies and/or facilitate personalised medicine. To do this, I will use the example of Crohn's disease-a chronic form of inflammatory bowel disease that has been one of the main success stories in complex disease genetics. Indeed, thanks to genetic studies, we now have a much more detailed understanding of the processes involved in Crohn's disease development, but still know relatively little about what determines the subsequent disease course (prognosis) and why this differs so considerably between individuals. I will discuss how we came to realise that genetic variation plays an important role in determining disease prognosis and how this has changed the way we think about Crohn's disease genetics. This will illustrate how phenotypic data can be used to leverage new insights from genetic data and will provide a broadly applicable framework that could yield new insights into the biology of multiple diseases.
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Affiliation(s)
- J C Lee
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK
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8
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Liefferinckx C, Franchimont D. Viewpoint: Toward the Genetic Architecture of Disease Severity in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2018; 24:1428-1439. [PMID: 29788122 DOI: 10.1093/ibd/izy109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is characterized by uneven disease courses with various clinical outcomes. A few prognostic markers of disease severity may help stratify patients and identify those who will benefit the most from early aggressive treatment. The concept of disease severity remains too broad and vague, mainly because the definition must embrace several disease mechanisms, mainly inflammation and fibrosis, with various rates of disease progression. The magnitude of inflammation is an obvious key driver of disease severity in IBD that ultimately influence disease behavior. Advances in the genetics underlying disease severity are currently emerging, but attempts to overlap the genetics of disease susceptibility and severity have until now been unsatisfactory, suggesting that the genetic architecture of disease severity may be distinct from the genetics of disease susceptibility. In this review, we report on the current knowledge on disease severity and on the main research venues to decipher the genetic architecture of disease severity.
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Affiliation(s)
| | - Denis Franchimont
- Department of Gastroenterology, Erasme Hospital, ULB, Brussels, Belgium
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9
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Gisbert-Ferrándiz L, Salvador P, Ortiz-Masiá D, Macías-Ceja DC, Orden S, Esplugues JV, Calatayud S, Hinojosa J, Barrachina MD, Hernández C. A Single Nucleotide Polymorphism in the Vitamin D Receptor Gene Is Associated With Decreased Levels of the Protein and a Penetrating Pattern in Crohn's Disease. Inflamm Bowel Dis 2018; 24:1462-1470. [PMID: 29788141 DOI: 10.1093/ibd/izy094] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Vitamin D signaling modulates inflammation through the vitamin D receptor (VDR). The synonymous single nucleotide polymorphism (SNP) rs731236, located in the VDR gene, has been associated with a higher risk of Crohn's disease (CD). We analyzed differences in VDR expression levels among CD patients who were homozygous for allelic variants in this SNP and their relevance for disease course. METHODS DNA was extracted from blood samples of CD patients, and SNP genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Fresh blood from patients was used to isolate peripheral blood mononuclear cells (PBMCs) or to determine the expression of adhesion molecules by flow cytometry. We analyzed the gene expression of VDR and several cytokines in PBMCs using real-time polymerase chain reaction and the protein levels of VDR, NFκB, and IκBα by immunoblot. In addition, we collected complete clinical data for a group of 103 patients, including age at diagnosis, disease location, and disease behavior to compare patient characteristics with respect to genotype. RESULTS We found that CD patients who were homozygous for the risk allele presented lower levels of VDR protein in PBMCs, and that this was associated with an upregulation of IL1β mRNA and activation of lymphocytic adhesion molecules. These patients had a higher risk of developing a B3-penetrating phenotype and of needing to undergo surgery. CONCLUSION Our data highlight the relevance of vitamin D/VDR signaling in modulating the subjacent inflammation that leads to CD-related complications.
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Affiliation(s)
| | - Pedro Salvador
- Departamento de Farmacología and CIBERehd, Valencia, Spain
| | - Dolores Ortiz-Masiá
- Departamento de Medicina and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | | | | | - Juan Vicente Esplugues
- Departamento de Farmacología and CIBERehd, Valencia, Spain.,FISABIO, Hospital Dr. Peset, Valencia, Spain
| | - Sara Calatayud
- Departamento de Farmacología and CIBERehd, Valencia, Spain
| | - Joaquín Hinojosa
- Servicio de Gastroenterología, Hospital de Manises, Valencia, Spain
| | | | - Carlos Hernández
- Departamento de Farmacología and CIBERehd, Valencia, Spain.,FISABIO, Hospital Dr. Peset, Valencia, Spain
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Tordjman M, Ouachee M, Bonnard A, Tilea B, Yakouben K, Viala J, Peuchmaur M, Berrebi D. Small bowel stenosis: a manifestation of chronic graft-versus-host disease in children? Hum Pathol 2018; 72:174-179. [DOI: 10.1016/j.humpath.2017.08.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 08/23/2017] [Accepted: 08/25/2017] [Indexed: 02/07/2023]
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11
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Verstockt B, Smith KGC, Lee JC. Genome-wide association studies in Crohn's disease: Past, present and future. Clin Transl Immunology 2018; 7:e1001. [PMID: 29484179 PMCID: PMC5822399 DOI: 10.1002/cti2.1001] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/20/2017] [Accepted: 11/23/2017] [Indexed: 12/12/2022] Open
Abstract
Over the course of the past decade, genome-wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL-17/IL-23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development - a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven 'within-cases' analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.
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Affiliation(s)
- Bram Verstockt
- Translational Research in Gastrointestinal Disorders (TARGID) ‐ IBDDepartment of Chronic Diseases, Metabolism and Ageing (CHROMETA)KU LeuvenLeuvenBelgium
- Department of Gastroenterology and HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of MedicineUniversity of Cambridge School of Clinical MedicineAddenbrooke's HospitalCambridgeUK
| | - Kenneth GC Smith
- Department of MedicineUniversity of Cambridge School of Clinical MedicineAddenbrooke's HospitalCambridgeUK
| | - James C Lee
- Department of MedicineUniversity of Cambridge School of Clinical MedicineAddenbrooke's HospitalCambridgeUK
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12
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Nuij VJAA, Peppelenbosch MP, van der Woude CJ, Fuhler GM. Genetic polymorphism in ATG16L1 gene is associated with adalimumab use in inflammatory bowel disease. J Transl Med 2017; 15:248. [PMID: 29228965 PMCID: PMC5725822 DOI: 10.1186/s12967-017-1355-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 11/29/2017] [Indexed: 01/06/2023] Open
Abstract
Background The role of single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease (IBD) is gaining interest. With the advent of novel therapies, personalized treatment in IBD is a future goal. We wondered whether IBD-associated SNPs are able to predict response to anti-TNFα treatment. Methods Data on treatment use and primary response, loss of response and side effects to anti-TNFα treatments were retrieved for 570 IBD patients. rs13361189 (IRGM), rs10210302 (ATG16L1), rs2066844, rs2066845, rs2066847 (NOD2), rs35873774 (XBP1), rs11175593 (LRRK2), rs11465804 (IL23R), rs2301436 (CCR6), rs744166 (STAT3) and rs4821544 (NCF4) SNP status were determined. Results No associations were found between genetic variants of the LRRK2, CCR6, IL23R and NCF4 genes and response to anti-TNFα. For NOD2 and XBP1 associations were found, however, these associations were not strong enough to survive multiple testing corrections. Strikingly, patients carrying the ATG16L1 T300A variant were more likely to be treated with adalimumab, even after correction for disease phenotype, disease behavior and age (p = 0.004, OR 2.8, CI 1.6–5.0). Conclusions Genetic polymorphisms in the known IBD-associated gene ATG16L1 correlate with requirement of treatment, suggesting a different IBD disease phenotype in these patients. Further investigation will need to elucidate the implications of these findings and identify the underlying disease characteristics. Electronic supplementary material The online version of this article (10.1186/s12967-017-1355-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- V J A A Nuij
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - M P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - C J van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - G M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
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13
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de Bruyn M, Vermeire S. NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease. Expert Opin Ther Targets 2017; 21:1123-1139. [DOI: 10.1080/14728222.2017.1397627] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Magali de Bruyn
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
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14
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Genetic Characterization and Influence on Inflammatory Bowel Disease Expression in a Diverse Hispanic South Florida Cohort. Clin Transl Gastroenterol 2017; 8:e87. [PMID: 28406493 PMCID: PMC5415895 DOI: 10.1038/ctg.2017.13] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 02/09/2017] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES Hispanics represent an understudied inflammatory bowel disease (IBD) population. Prior studies examining genetic predisposition to IBD in Hispanics are limited. In this study, we examined whether European-derived IBD variants confer risk in Hispanics and their influence on IBD phenotype in Hispanics compared to non-Hispanic whites (NHW). METHODS Self-identified Hispanics and NHWs with IBD were included. Hispanic controls were included for our genetic analyses. We performed single-variant testing at previously identified Crohn's disease (CD) and ulcerative colitis (UC) IBD variants in Hispanic cases and controls. These risk variants were used to compute individual genetic risk scores. Genetic risk scores and phenotype associations were compared between Hispanic and NHW. RESULTS A total of 1,115 participants were included: 698 controls and 417 IBD patients (230 Hispanics). We found evidence of association within our Hispanic cohort at 22 IBD risk loci, with ~76% of the risk loci demonstrating over-representation of the European risk allele; these included loci corresponding to IL23R and NOD2 genes. CD genetic risk score for Hispanics (199.67) was similar to the score for NHW (200.33), P=0.51; the same was true in UC. Genetic risk scores did not predict IBD phenotype or complications in Hispanics or NHW except for a younger age of CD onset in Hispanics (P=0.04). CONCLUSIONS This study highlights the fundamental importance of these loci in IBD pathogenesis including in our diverse Hispanic population. Future studies looking at non-genetic mechanisms of disease are needed to explain differences in age of presentation and phenotype between Hispanics and NHW.
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15
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Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol Hepatol 2017; 2:224-234. [PMID: 28404137 DOI: 10.1016/s2468-1253(16)30111-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/02/2016] [Accepted: 09/02/2016] [Indexed: 01/11/2023]
Abstract
The study of the genetic underpinnings of inflammatory bowel disease has made great progress since the identification of NOD2 as a major susceptibility gene. Novel genotyping and sequencing technologies have led to the discovery of 242 common susceptibility loci, 45 of which have been fine-mapped to statistically conclusive causal variants; 50 genes associated with very-early-onset inflammatory disease have been identified. The evolving genetic architecture of inflammatory bowel disease has deepened our understanding of its pathogenesis through identification of major disease associated pathways-knowledge that has the potential to indicate novel drug targets or markers for personalised medicine. However, many causal variants have yet to be identified, and a large proportion of missing heritability still needs to be accounted for. In addition, the medical and scientific communities are probably not yet fully harnessing the power of these genetic discoveries.
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Lee JC, Biasci D, Roberts R, Gearry RB, Mansfield JC, Ahmad T, Prescott NJ, Satsangi J, Wilson DC, Jostins L, Anderson CA, the UK IBD Genetics Consortium, Traherne JA, Lyons PA, Parkes M, Smith KG. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nat Genet 2017; 49:262-268. [PMID: 28067912 PMCID: PMC5730041 DOI: 10.1038/ng.3755] [Citation(s) in RCA: 192] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/29/2016] [Indexed: 12/11/2022]
Abstract
For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
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Affiliation(s)
- James C. Lee
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Daniele Biasci
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Rebecca Roberts
- University of Otago, Department of Medicine, Christchurch, New Zealand
| | - Richard B. Gearry
- University of Otago, Department of Medicine, Christchurch, New Zealand
| | | | - Tariq Ahmad
- University of Exeter Medical School, Exeter, UK
| | - Natalie J. Prescott
- Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King’s College London, 8th Floor Guy’s Tower, Guy’s Hospital, London, UK
| | - Jack Satsangi
- Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - David C. Wilson
- Paediatric Gastroenterology and Nutrition, Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Royal Hospital for Sick Children, Edinburgh, UK
| | - Luke Jostins
- Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK
| | - Carl A. Anderson
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
| | | | | | - Paul A. Lyons
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Miles Parkes
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Kenneth G.C. Smith
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
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17
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Navarra CO, Robino A, Pirastu N, Bevilacqua L, Gasparini P, Di Lenarda R, Crovella S. Caries and Innate Immunity: DEFB1 Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy. Caries Res 2016; 50:589-594. [DOI: 10.1159/000450965] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/20/2016] [Indexed: 11/19/2022] Open
Abstract
Background: The DEFB1 gene, encoding for the constitutively expressed human β-defensin 1 (hBD1) antimicrobial peptide is a potential candidate when studying genetic susceptibility to caries. DEFB1 genetic variations have been reported as contributing to hBD1 production impairment, leading to a greater susceptibility to be infected by oral pathogens, also leading to periodontitis. Methods: We analysed 5 DEFB1 polymorphisms, namely 3 functional single-nucleotide polymorphisms (SNPs) at the 5′-untranslated region (UTR), -52G>A (rs1799946), -44C>G (rs1800972), and -20G>A (rs11362), 2 SNPs at the 3′-UTR, c*5G>A (rs1047031) and c*87A>G (rs1800971) SNP located in potential miRNA binding sites, looking for possible correlations with the risk to develop caries in 654 adult subjects from isolated populations of north-eastern Italy. Dental caries prevalence was evaluated with the DMFT (decayed, missing, filled teeth) index, calculated after an accurate oral examination. DEFB1 SNP genotyping was performed with an Illumina 370k high-density SNP array. Results: Two DEFB1 SNPs were significantly associated with the DMFT index: the strongest association emerged from rs11362 SNP (p = 0.008). In particular G/G homozygous individuals showed a higher DMFT index compared to both G/A heterozygous and A/A homozygous individuals; rs1799946 SNP was also significantly associated with DMFT (p = 0.030), and individuals homozygous for the T allele had a higher DMFT value compared to heterozygous C/T and homozygous C/C individuals. Conclusions: Our study replicated, on a larger number of individuals, previous findings showing the association between two 5′-UTR SNPs in the DEFB1 gene and DMFT, suggesting that these polymorphisms could be considered as potential markers for assessing the risk to develop caries.
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Zhang BB, Liang Y, Yang B, Tan YJ. Association between ATG16L1 gene polymorphism and the risk of Crohn's disease. J Int Med Res 2016; 45:1636-1650. [PMID: 27698206 PMCID: PMC5805181 DOI: 10.1177/0300060516662404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective To perform a meta-analysis to evaluate studies investigating the association
between ATG16L1 gene polymorphism and Crohn’s disease. Methods PubMed, Embase and Web of Science databases were searched for all studies
focusing on the association of ATG16L1 and Crohn’s disease.
Combined odds ratios with 95% confidence intervals were calculated for four
genetic models (allelic model: G allele versus A allele; additive model: GG
versus AA; dominant model: GA + GG versus AA; recessive model: GG versus
GA + AA) using either a random effects or fixed effects model. Results A total of 47 case–control studies involving 18 638 cases and 30 181 controls
were included in the final meta-analysis. There was a significant
association between ATG16L1 and Crohn’s disease for all
four genetic models. Significant associations were also shown in subgroup
analyses when stratified by study design (population- or
hospital-based). Conclusion In this meta-analysis, the ATG16L1 genotype was
significantly associated with the risk of developing Crohn’s disease.
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Affiliation(s)
- Bei-Bei Zhang
- 1 Department of Medical Affairs, General Hospital of PLA Chengdu Military Area Command, Chengdu, China
| | - Yu Liang
- 2 Department of Thoracic Surgery, General Hospital of PLA Chengdu Military Area Command, Chengdu, China
| | - Bo Yang
- 1 Department of Medical Affairs, General Hospital of PLA Chengdu Military Area Command, Chengdu, China
| | - Ying-Jun Tan
- 1 Department of Medical Affairs, General Hospital of PLA Chengdu Military Area Command, Chengdu, China
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Epistatic interaction between TLR4 and NOD2 in patients with Crohn's Disease: relation with risk and phenotype in a Spanish cohort. Immunobiology 2016; 221:927-33. [PMID: 27290609 DOI: 10.1016/j.imbio.2016.05.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 05/18/2016] [Accepted: 05/27/2016] [Indexed: 01/11/2023]
Abstract
Crohn's Disease is one of the two major forms of the Inflammatory Bowel Diseases and, although the etiology is not completely understood, the confluence of environmental and genetic factors has been demonstrated. The aim of this study was to determine the distribution of TLR4 variants in a Spanish cohort of Crohn's Disease patients and their relation with phenotype and common NOD2 variants. A total of 371 Crohn's Disease (CD) patients and 636 healthy controls (HC) were included. Single Nucleotide Polimorphisms (SNPs) in TLR4 (D299G and T399I) and NOD2 (R702W and G908R) detection was performed by a Taqman(®) Allelic Discrimination Assay. 1007insC NOD2 variant was analyzed using a PCR combined with fluorescent technology and the different alleles were determined depending on the PCR products size. D299G and T399I were related to CD only in patients carrying NOD2 variants (NOD2+/TLR4+ haplotype) (p=0.036; OR=1.924), increasing the risk to develop CD when 1007insC and TLR4 variants were both present (OR=4.886). We also described a strong association between mutant NOD2 and CD risk (p<0.001, OR=3.214). R702W, G908R and 1007insC were associated when they were considered separately (p<0.001; p=0.002; p<0.001, respectively). Moreover, the patients carrying any mutant D299G or T399I polymorphisms were predisposed to develop a stricturing disease (p=0.013; OR=2.391), especially in the presence of NOD2 mutation (p=0.002; OR=4.989). In this study, ileal disease was also associated with the presence of at least one NOD2 susceptibility allele (p=0.001; OR=3.838) and, the risk of ileal CD was increased if TLR4 variants were presents (p<0.050; OR=4.160). TLR4 variants were related to bowel perforation, independently of NOD2.
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Kingsley MJ, Abreu MT. A Personalized Approach to Managing Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2016; 12:308-15. [PMID: 27499713 PMCID: PMC4973561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The management of inflammatory bowel disease (IBD) requires a personalized approach to treat what is a heterogeneous group of patients with inherently variable disease courses. In its current state, personalized care of the IBD patient involves identifying patients at high risk for rapid progression to complications, selecting the most appropriate therapy for a given patient, using therapeutic drug monitoring, and achieving the individualized goal that is most appropriate for that patient. The growing body of research in this area allows clinicians to better predict outcomes for individual patients. Some paradigms, especially within the realm of therapeutic drug monitoring, have begun to change as therapy is targeted to individual patient results and goals. Future personalized medical decisions may allow specific therapeutic plans to draw on serologic, genetic, and microbial data for Crohn's disease and ulcerative colitis patients.
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Affiliation(s)
- Michael J Kingsley
- Dr Kingsley is a gastroenterology fellow at the University of Miami Miller School of Medicine and Jackson Memorial Hospital in Miami, Florida. Dr Abreu is a professor of medicine, professor of microbiology and immunology, and chief of the Division of Gastroenterology at the University of Miami Miller School of Medicine
| | - Maria T Abreu
- Dr Kingsley is a gastroenterology fellow at the University of Miami Miller School of Medicine and Jackson Memorial Hospital in Miami, Florida. Dr Abreu is a professor of medicine, professor of microbiology and immunology, and chief of the Division of Gastroenterology at the University of Miami Miller School of Medicine
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Abstract
Inflammation in inflammatory bowel diseases (IBD) has been linked to a loss of tolerance to self-antigens suggesting the existence of autoantibodies in specific disease phenotypes. However, the lack of clearly defined autoantigenic targets has slowed down research. Genome-wide association studies have identified an impressive number of immune-related susceptibility loci for IBD with no clearly discernible pattern among them. Growing evidence supports the hypothesis that innate immune responses to a low-diversity and impaired gut microbiota may be of key importance in initiating and perpetuating chronic inflammation in IBD. Increasing evidence suggests that reduced microbial diversity and microbial-mucosal epithelium interaction (including adhesion and clearance) are critically involved in IBD pathogenesis. Along these lines the discovery of autoantigenic targets in Crohn's disease (CD) has refocused research in IBD on the possible role of autoimmune responses. The identification of the major zymogen granule membrane glycoprotein 2 (GP2) as an autoantigen in CD patients and its proposed role in the sensing of the microbiota lends credence to this trend. Loss of tolerance to GP2 occurs in up to 40% of patients with CD. Corresponding autoantibodies appear to be associated with distinct disease courses (types or phenotypes) in CD. Here, we critically review autoantibodies in CD for their impact on clinical practice and future IBD research. The immunomodulatory role of GP2 in innate and adaptive intestinal immunity is also discussed.
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Xu WD, Xie QB, Zhao Y, Liu Y. Association of Interleukin-23 receptor gene polymorphisms with susceptibility to Crohn's disease: A meta-analysis. Sci Rep 2015; 5:18584. [PMID: 26678098 PMCID: PMC4683513 DOI: 10.1038/srep18584] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 11/20/2015] [Indexed: 02/05/2023] Open
Abstract
Studies investigating the association between Interleukin-23 receptor (IL-23R) gene polymorphisms and Crohn’s disease (CD) report conflicting results. Thus, a meta-analysis was carried out to assess the association between the IL-23R polymorphisms and CD. A systematic literature search was conducted to identify all relevant studies. Pooled odds ratio (ORs) with 95% confidence interval (CIs) was used to estimate the strength of association. Finally, a total of 60 case-control studies in 56 articles, involving 22,820 CD patients and 27,401 healthy controls, were included in the meta-analysis. Overall, a significant association was found between all CD and the rs7517847 polymorphism (OR = 0.699, 95% CI = 0.659 ~ 0.741, P < 0.001). Meta-analysis of the rs11209026, rs1343151, rs10489629 and rs11465804 polymorphisms indicated the same pattern as for rs7517847. Meta-analysis showed an association between the rs10889677A allele and CD (OR = 1.393, 95% CI = 1.328 ~ 1.461, P < 0.001). Similarly, meta-analysis of the rs2201840, rs1004819, rs1495965 and rs11209032 polymorphisms revealed the same pattern as that shown by meta-analysis of rs10889677. Stratification by ethnicity revealed that IL-23R gene polymorphisms were associated with CD in the Caucasian group, but not in Asians. In summary, the meta-analysis suggests a significant association between IL-23R polymorphisms and CD, especially in Caucasians.
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Affiliation(s)
- Wang-Dong Xu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
| | - Qi-Bing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
| | - Yi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
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Association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease risk in Caucasian: a meta-analysis. Inflamm Res 2015; 64:825-31. [PMID: 26289093 DOI: 10.1007/s00011-015-0866-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Revised: 07/15/2015] [Accepted: 08/04/2015] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE Published studies on the association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease (IBD) risk in Caucasian have yielded conflicting results. The present study aimed to provide more reliable conclusions by conducting a meta-analysis. METHODS All eligible studies were extracted from Wiley Online Library, Chinese National Knowledge Infrastructure and PubMed databases. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations between rs4821544T/C polymorphism and IBD risk in Caucasian. RESULTS A total of 13 case-control studies comprising 7441 Crohn's disease (CD) patients, 2565 ulcerative colitis (UC) patients and 8315 controls were included in this meta-analysis. Significant associations were found between CD and the rs4821544T/C polymorphism in three genetic models (C vs T: OR = 1.11, 95 % CI: 1.06, 1.16, P = 0.000; CC vs TT: OR = 1.31, 95 % CI: 1.18, 1.45, P = 0.000; CC/TC vs TT: OR = 1.07, 95 % CI: 1.01, 1.13, P = 0.014; CC vs TC/TT OR = 1.28, 95 % CI: 1.16, 1.42, P = 0.000). However, significant associations were not found in UC under any genetic models (C vs T: OR = 1.04, 95 % CI: 0.97, 1.11, P = 0.264; CC vs TT: OR = 1.10, 95 % CI: 0.93, 1.30, P = 0.284; TC vs TT: OR = 1.04, 95 % CI: 0.95, 1.13, P = 0.429; CC/TC vs TT: OR = 1.04, 95 % CI: 0.95, 1.13, P = 0.390; CC vs TC/TT OR = 1.07, 95 % CI: 0.91, 1.26, P = 0.409). CONCLUSION This meta-analysis suggested that the rs4821544T/C polymorphism was associated with CD, but not UC in Caucasian.
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Liu Z, Shen B. Overcoming difficulty in diagnosis and differential diagnosis of Crohn's disease: the potential role of serological and genetic tests. Expert Rev Mol Diagn 2015; 15:1133-41. [PMID: 26295589 DOI: 10.1586/14737159.2015.1068121] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Crohn's disease (CD) represents a heterogeneous group of chronic inflammatory disorders with various phenotypes. Establishing a definite diagnosis of CD should be based upon a combined assessment of clinical, endoscopic, radiological and pathological features. Although segmental disease distribution, transmural inflammation and non-caseating epithelioid granulomas have been considered as a 'hallmarks' for CD, clear diagnosis of CD in some patients has been challenging, due to overlapping endoscopic, radiographic and histologic features with other inflammatory bowel disease-like conditions. Laboratory markers (serological and genetic tests) may provide additional clues for the diagnosis and differential diagnosis of CD. This review focuses on the application of the currently available serological and genomic markers and in diagnosis and differential diagnosis of CD.
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Affiliation(s)
- Zhaoxiu Liu
- a 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
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Zhang JX, Song J, Wang J, Dong WG. JAK2 rs10758669 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. Inflammation 2015; 37:793-800. [PMID: 24385239 DOI: 10.1007/s10753-013-9798-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In this meta-analysis, we aimed to clarify the impact of Janus kinase 2 (JAK2) rs10758669 polymorphisms on ulcerative colitis (UC) and Crohn's disease (CD) risk. Data were extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95%CIs) were calculated. Eleven studies with 7009 CD patients, 7929 UC patients, and 19235 controls were included. The results showed that JAK2 rs10758669 polymorphism was associated with CD (AC vs. AA, OR = 1.16, 95%CI, 1.08-1.24; CC vs. AA, OR = 1.29, 95%CI, 1.17-1.43; AC + CC vs. AA, OR = 1.19, 95%CI, 1.11-1.27; CC vs. AA + AC, OR = 1.19, 95%CI, 1.09-1.31; C vs. A, OR = 1.14, 95%CI, 1.09-1.20) and UC susceptibility (AC vs. AA, OR = 1.14, 95%CI, 1.06-1.22; CC vs. AA, OR = 1.33, 95%CI, 1.20-1.47; AC + CC vs. AA, OR = 1.18, 95%CI, 1.10-1.27; CC vs. AA + AC, OR = 1.24, 95%CI, 1.12-1.36; C vs. A, OR = 1.15, 95%CI, 1.10-1.21). But no significant association was found between JAK2 rs10758669 polymorphism with CD in Asian. Either in adult-onset group or multi-age group, hospital-based group or population-based group, JAK2 rs10758669 polymorphism was associated with CD and UC susceptibility. This meta-analysis indicated that JAK2 rs10758669 polymorphism was a risk factor both for CD and UC, especially in Caucasian. The differences in age of onset and study design did not influence the associations obviously. Gene-gene and gene-environment interactions should be investigated in the future.
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Affiliation(s)
- Ji-Xiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
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Abstract
The disease spectrum and natural course of Crohn's disease and ulcerative colitis are highly variable. The majority of Crohn's disease patients will require surgery at a certain stage in their disease compared to only a fraction of the ulcerative colitis patients. Similarly, some patients are destined to experience an indolent disease course while others will require early intensive therapy. Ideally, these subtypes of patients should be identified as early as possible with the help of reliable prognostic factors in order to guide personalized therapeutic decisions. In this review, the authors focused on the most relevant reports on the use of different prognostic factors to predict disease course, postoperative recurrence and response to therapy in patients with inflammatory bowel disease. The last 15 years have seen a wealth of novel genetic and serological markers of disease severity. Nevertheless, none of these markers have proven to be superior to careful clinical phenotyping and endoscopic features early in the disease course. Future attempts should apply an integrated approach that unites clinical, serological and (epi)genetic information with environmental influences, with a clear focus on the microbiome to ultimately identify molecular-based and clinically relevant subgroups.
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Palmela C, Torres J, Cravo M. New Trends in Inflammatory Bowel Disease. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2015; 22:103-111. [PMID: 28868386 PMCID: PMC5579988 DOI: 10.1016/j.jpge.2015.03.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 03/12/2015] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disease of the gastrointestinal (GI) tract. In the past decade a shift in the treatment paradigm of IBD has ensued. The availability of drugs capable of inducing mucosal healing, combined with the recognition that IBD is not an intermittent disease, but rather a progressive one causing bowel damage and disability, led us to a more stringent strategy. Tailored therapy with more aggressive treatment in high-risk patients, treating beyond symptoms, intervening early before damage occurs, optimizing therapeutic regimens, and actively pursuing sustained remission and sustained control of inflammation are strategies that are slowly being incorporated in our clinical practice. Furthermore, new drugs targeting different immunological pathways, such as vedolizumab, have recently been approved and therefore more therapeutic resources for patients failing anti-tumour necrosis factor alpha (anti-TNFα) agents will be available. The future years look promising for IBD. Hopefully the new trends in IBD management, combined with new drugs, will make possible to change the course of disease and provide better therapy and quality of life for patients suffering from this disabling disease.
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Affiliation(s)
| | | | - Marilia Cravo
- Gastroenterology Department, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
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28
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Alonso A, Domènech E, Julià A, Panés J, García-Sánchez V, Mateu PN, Gutiérrez A, Gomollón F, Mendoza JL, Garcia-Planella E, Barreiro-de Acosta M, Muñoz F, Vera M, Saro C, Esteve M, Andreu M, Chaparro M, Manyé J, Cabré E, López-Lasanta M, Tortosa R, Gelpí JL, García-Montero AC, Bertranpetit J, Absher D, Myers RM, Marsal S, Gisbert JP. Identification of risk loci for Crohn's disease phenotypes using a genome-wide association study. Gastroenterology 2015; 148:794-805. [PMID: 25557950 DOI: 10.1053/j.gastro.2014.12.030] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 12/16/2014] [Accepted: 12/19/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. METHODS We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes (P < 2 × 10(-4)) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. RESULTS We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 × 10(-8)), disease location (Pcombined = 1.3 × 10(-6)), mild disease course (Pcombined = 5.94 × 10(-7)), and erythema nodosum (Pcombined = 2.27 × 10(-6)), respectively. CONCLUSIONS In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.
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Affiliation(s)
- Arnald Alonso
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain; Department of Enginyeria de Sistemes, Automática i Informàtica Industrial, Polytechnic University of Catalonia, Barcelona, Spain
| | - Eugeni Domènech
- Gastroenterology and Hepatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
| | - Antonio Julià
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Julián Panés
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Gastroenterology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Valle García-Sánchez
- Digestive System Service, Universidad de Córdoba/Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Pilar Nos Mateu
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Digestive Medicine Service, Hospital la Fe, Valencia, Spain
| | - Ana Gutiérrez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Gastroenterology Service, Hospital General de Alicante, Alicante, Spain
| | - Fernando Gomollón
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Digestive System Service, Hospital Clínico Universitario, Zaragoza, Spain
| | - Juan L Mendoza
- Gastroenterology Service, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Fernando Muñoz
- Gastroenterology Service, Complejo Hospitalario de León, León, Spain
| | - Maribel Vera
- Gastroenterology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Cristina Saro
- Internal Medicine Service, Hospital de Cabueñes, Gijón, Spain
| | - Maria Esteve
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Gastroenterology Service, Hospital Universitari Mutua de Terrassa, Barcelona, Spain
| | - Montserrat Andreu
- Department of Gastroenterology, Institut Hospital del Mar d'Investigacions Mèdiques, Institute of Research Hospital del Mar, Parc de Salut Mar, Pompeu Fabra University, Barcelona, Spain
| | - Maria Chaparro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Gastroenterology Service, Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain
| | - Josep Manyé
- Gastroenterology and Hepatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Eduard Cabré
- Gastroenterology and Hepatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - María López-Lasanta
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Raül Tortosa
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Josep Lluís Gelpí
- Life Sciences, Barcelona Supercomputing Center, National Institute of Bioinformatics, Barcelona, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
| | | | | | - Devin Absher
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
| | - Richard M Myers
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
| | - Sara Marsal
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
| | - Javier P Gisbert
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Gastroenterology Service, Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain
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Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease. J Invest Dermatol 2015; 135:1969-1976. [PMID: 25789703 DOI: 10.1038/jid.2015.103] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 02/18/2015] [Accepted: 03/03/2015] [Indexed: 02/08/2023]
Abstract
Psoriasis is clinically heterogeneous, and symptoms can vary from mild almost cosmetic symptoms to severe disease requiring systemic therapy. Biomarkers predicting disease development are lacking. Herein we explored the genetic background in two polarized cohorts of carefully phenotyped patients with long-term follow-up: consistent mild phenotype (n=696) and severe disease course requiring systemic therapy (n=715). All patients were treated at the same dermatology department ensuring homogenous assessment. Genotyping included known psoriasis-associated variants, with special focus on the IL-23 and NF-κB pathways. A case-case study comparing severe and mild psoriasis phenotypes, controlling for age at disease onset and gender, revealed significant differences between the two groups for SNPs in IL23R, NFKB1, IL21, IL12B, NFKBIL1 and IL23A. HLA-C*06 associated equally in the mild and severe disease cohorts. Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis. No protective gene was identified in the mild cohort, suggesting that current screens have primarily identified psoriasis variants associated with a more severe phenotype. These results demonstrate the importance of careful phenotyping and long-term clinical follow-up in genetic studies.
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Frémond ML, Viala J, Tréton X, Roy M, Berrebi D, Gottrand F, Bonnard A, Martinez-Vinson C, Hugot JP. Digestive perianastomotic ulcerations and Crohn's disease. J Crohns Colitis 2014; 8:1624-31. [PMID: 25107846 DOI: 10.1016/j.crohns.2014.06.011] [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: 02/18/2014] [Revised: 06/29/2014] [Accepted: 06/30/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Digestive perianastomotic ulcerations (DPAU) have been occasionally reported as late complications of neonatal or childhood surgery. METHODS We report here a series of 14 new cases. RESULTS Cases were revealed by severe anemia, diarrhea, abdominal pain and growth failure in average 11.5 years after surgery. Ulcerations were most often multiple (n=11), located on the upper part of ileocolonic anastomoses (n=12) and difficult to treat. No granulomas were seen but lymphoid follicles were frequent. In addition, either ASCA or ANCA were positive in 4/9 tested patients and 8/11 genotyped patients exhibited a NOD2 mutation (P<0.0002 when compared to French healthy controls). CONCLUSION Altogether, these findings argue for common physiopathological features between DPAU and Crohn's disease and for a prospective follow-up of selected operated children to explore the early events involved in gut inflammatory lesions.
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Affiliation(s)
- Marie-Louise Frémond
- Assistance Publique-Hôpitaux de Paris, Services des Maladies Digestives et Respiratoires de l'enfant, Service de Chirurgie Digestive et Service de Cytologie et Pathologie, Hôpital Robert Debré, 75019 Paris, France
| | - Jérome Viala
- Assistance Publique-Hôpitaux de Paris, Services des Maladies Digestives et Respiratoires de l'enfant, Service de Chirurgie Digestive et Service de Cytologie et Pathologie, Hôpital Robert Debré, 75019 Paris, France; Université Paris-Diderot UMR 1149, Labex Inflamex, 75018 Paris, France; INSERM UMR1149, Centre de Recherche sur l'inflammation Paris Montmartre, 75018 Paris, France
| | - Xavier Tréton
- Université Paris-Diderot UMR 1149, Labex Inflamex, 75018 Paris, France; INSERM UMR1149, Centre de Recherche sur l'inflammation Paris Montmartre, 75018 Paris, France; Assistance Publique-Hôpitaux de Paris, Service de Gastroentérologie, Hôpital Beaujon, 92000 Clichy, France
| | - Maryline Roy
- Université Paris-Diderot UMR 1149, Labex Inflamex, 75018 Paris, France; INSERM UMR1149, Centre de Recherche sur l'inflammation Paris Montmartre, 75018 Paris, France
| | - Dominique Berrebi
- Assistance Publique-Hôpitaux de Paris, Services des Maladies Digestives et Respiratoires de l'enfant, Service de Chirurgie Digestive et Service de Cytologie et Pathologie, Hôpital Robert Debré, 75019 Paris, France; Université Paris-Diderot UMR 1149, Labex Inflamex, 75018 Paris, France; INSERM UMR1149, Centre de Recherche sur l'inflammation Paris Montmartre, 75018 Paris, France
| | | | - Arnaud Bonnard
- Assistance Publique-Hôpitaux de Paris, Services des Maladies Digestives et Respiratoires de l'enfant, Service de Chirurgie Digestive et Service de Cytologie et Pathologie, Hôpital Robert Debré, 75019 Paris, France; Université Paris-Diderot UMR 1149, Labex Inflamex, 75018 Paris, France
| | - Christine Martinez-Vinson
- Assistance Publique-Hôpitaux de Paris, Services des Maladies Digestives et Respiratoires de l'enfant, Service de Chirurgie Digestive et Service de Cytologie et Pathologie, Hôpital Robert Debré, 75019 Paris, France
| | - Jean-Pierre Hugot
- Assistance Publique-Hôpitaux de Paris, Services des Maladies Digestives et Respiratoires de l'enfant, Service de Chirurgie Digestive et Service de Cytologie et Pathologie, Hôpital Robert Debré, 75019 Paris, France; Université Paris-Diderot UMR 1149, Labex Inflamex, 75018 Paris, France; INSERM UMR1149, Centre de Recherche sur l'inflammation Paris Montmartre, 75018 Paris, France.
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Zhang J, Wu J, Peng X, Song J, Wang J, Dong W. Associations between STAT3 rs744166 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. PLoS One 2014; 9:e109625. [PMID: 25286337 PMCID: PMC4186844 DOI: 10.1371/journal.pone.0109625] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 09/09/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Many studies have investigated the associations between the signal transducer and activator of transcription 3 (STAT3) in the susceptibility to ulcerative colitis (UC) and Crohn's disease (CD). However, the results remain inconsistent. This meta-analysis determined the risk of STAT3 rs744166 polymorphism-conferred UC and CD susceptibility. MATERIALS AND METHODS Electronic databases, including PubMed, EMBASE and the Cochrane Library, were searched for all eligible studies that evaluated the association between STAT3 rs744166 polymorphisms with UC and CD risk up to August 21, 2014. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed- or random-effects models. RESULTS Twelve studies containing 10298 patients with CD, 4244 patients with UC and 11191 controls were included in this meta-analysis. The results indicated that the STAT3 rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, OR = 1.20, 95%CI, 1.11-1.30, I2 = 0%, Punadjusted<0.00001, PBonferroni<0.00005, PFDR<0.00001; UC: GA+AA vs. GG, OR = 1.21, 95%CI, 1.08-1.36, I2 = 1%, Punadjusted = 0.001, PBonferroni = 0.005, PFDR = 0.00125). In subgroup analyses by ethnicity, the significant association was found only among Caucasians. However, when grouped by age of onset, positive associations were found both among adults and children. In addition, when stratified by study design and genotyping methods, the risk of CD was significantly associated with the STAT3 rs744166 polymorphism in hospital-based and population-based groups and in SNP Array and SNPlex groups. For UC, significant associations were also found in population-based, PCR-RFLP and SNPlex groups. Moreover, these findings were sufficiently robust to withstand the Bonferroni correction and false discovery rate (FDR). CONCLUSION This meta-analysis indicates that carriers of the STAT3 rs744166 'A' allele have a significantly greater risk of CD and UC, especially among Caucasians.
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Affiliation(s)
- Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jianhong Wu
- Wuhan medical treatment center, Wuhan, Hubei Province, China
| | - Xiulan Peng
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei Province, China
| | - Jia Song
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- * E-mail:
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Zhang J, Zhang J, Wu D, Wang J, Dong W. Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: A meta-analysis. Autoimmunity 2014; 47:512-8. [DOI: 10.3109/08916934.2014.930735] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University
Wuhan, Hubei ProvinceChina
| | - Jihui Zhang
- Advanced Training Center of State Grid Corporation of China
Sibozi, Qinghe, Haidian District, BeijingChina
| | - Dandan Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University
Wuhan, Hubei ProvinceChina
| | - Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University
Wuhan, Hubei ProvinceChina
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University
Wuhan, Hubei ProvinceChina
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Abstract
The expanding knowledge of the role of genetic variants involved in the susceptibility to IBD heralds an era of disease categorization beyond Crohn's disease and ulcerative colitis. A more robust molecular definition of the spectrum of IBD subtypes is likely to be based on specific molecular pathways that determine not only disease susceptibility but also disease characteristics such as location, natural history and therapeutic response. Evolving diagnostic panels for IBD will include clinical variables and genetic markers as well as other indicators of gene function and interaction with environmental factors, such as the microbiome. Multimodal algorithms that combine clinical, serologic and genetic information are likely to be useful in predicting disease course. Variation in IBD-susceptibility and drug-related pathway genes seems to influence the response to anti-TNF therapy. Furthermore, gene expression signatures and composite models have both shown promise as predictors of therapeutic response. Ultimately, models based on combinations of genotype and gene expression data with clinical, biochemical, serological, and microbiome data for clinically meaningful subgroups of patients should permit the development of tools for individualized risk stratification and treatment selection.
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Long WY, Chen L, Zhang CL, Nong RM, Lin MJ, Zhan LL, Lv XP. Association between NOD2/CARD15 gene polymorphisms and Crohn's disease in Chinese Zhuang patients. World J Gastroenterol 2014; 20:4737-4744. [PMID: 24782627 PMCID: PMC4000511 DOI: 10.3748/wjg.v20.i16.4737] [Citation(s) in RCA: 12] [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: 10/31/2013] [Revised: 01/06/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the relationship between the P268S, JW1 and N852S polymorphisms and Crohn’s disease (CD) susceptibility in Zhuang patients in Guangxi, China.
METHODS: Intestinal tissues from 102 Zhuang [48 CD and 54 ulcerative colitis (UC)] and 100 Han (50 CD and 50 UC) unrelated patients with inflammatory bowel disease and 72 Zhuang and 78 Han unrelated healthy individuals were collected in the Guangxi Zhuang Autonomous Region from January 2009 to March 2013. Genomic DNA was extracted using the phenol chloroform method. The P268S, JW1 and N852S polymorphisms were amplified using polymerase chain reaction (PCR), detected by restriction fragment length polymorphism (RFLP), and verified by gene sequencing.
RESULTS: Heterozygous mutation of P268S in the NOD2/CARD15 gene was detected in 10 CD cases (six Zhuang and four Han), two Han UC cases, and one Zhuang healthy control, and P268S was strongly associated with the Chinese Zhuang and Han CD populations (P = 0.016 and 0.022, respectively). No homozygous mutant P268S was detected in any of the groups. No significant difference was found in P268S genotype and allele frequencies between UC and control groups (P > 0.05). Patients with CD who carried P268S were likely to be ≤ 40 years of age (P = 0.040), but were not significantly different with regard to race, lesion site, complications, and other clinical features (P > 0.05). Neither JW1 nor N852S polymorphisms of the NOD2/CARD15 gene were found in any of the subjects (P > 0.05).
CONCLUSION: P268S polymorphism may be associated with CD susceptibility in the Zhuang population in the Guangxi Zhuang Autonomous Region, China. In contrast, JW1 and N852S polymorphisms may not be related to CD susceptibility in these patients.
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Abstract
Crohn's disease (CrD) is a chronic relapsing inflammatory bowel disease (IBD) potentially affecting any portion of the gastrointestinal tract from the mouth to the anus. CrD usually manifests between 15 and 30 years of age and presents typically with abdominal pain, fever, bloody or non-bloody diarrhoea, and weight loss. Paediatric patients may show failure to thrive, growth impairment, and delayed puberty additionally. Extraintestinal manifestations like arthritis, uveitis, and erythema nodosum are diagnosed in almost half of the patients. CrD is characterized by a discontinuous and ulcerous transmural inflammation often involving the ileocaecal region and leading to a stricturing or even fistulising phenotype in up to 50% of patients finally. Incidence and prevalence of CrD have been rising worldwide over the past decades. Although many details of the pathophysiology of CrD have been elucidated, no common aetiopathogenic model exists for all forms of CrD, presenting more an umbrella term for a phenotypically and genotypically heterogeneous clinical condition. In CrD, we see an inappropriate response of the innate and/or adaptive immune system to the intestinal microbiota in genetically predisposed individuals. The diagnosis of CrD is based mainly on patient's history and clinical examination and supported by serologic, radiologic, endoscopic, and histologic findings. Antibodies to Saccharomyces cerevisiae and autoantigenic targets such as glycoprotein 2 may aid in differentiating CrD from UC. Their single use, however, is limited by low sensitivity requiring antibody profiling for an appropriate serologic diagnosis. This review focuses on diagnostic and classification criteria of CrD.
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Affiliation(s)
- Martin W Laass
- Department of Paediatrics, Medical Faculty of the Technical University of Dresden, Dresden, Germany
| | - Dirk Roggenbuck
- Faculty of Science, Brandenburg Technical University Cottbus-Senftenberg, Senftenberg, Germany; GA Generic Assays GmbH, Dahlewitz, Germany
| | - Karsten Conrad
- Institute of Immunology, Medical Faculty of the Technical University of Dresden, Germany.
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Differential effect of genetic burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort. Am J Gastroenterol 2014; 109:395-400. [PMID: 24419484 PMCID: PMC4225079 DOI: 10.1038/ajg.2013.464] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 12/17/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. METHODS The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 inflammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles. RESULTS Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (Ptrend=0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (Ptrend <0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC. CONCLUSIONS Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history.
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Long WY, Zhan LL, Chen L, Lv XP. Association of 10q21 gene rs10761659 polymorphism with susceptibility to inflammatory bowel disease in a Guangxi Zhuang population. Shijie Huaren Xiaohua Zazhi 2013; 21:3146-3152. [DOI: 10.11569/wcjd.v21.i29.3146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the association of 10q21 gene rs10761659 polymorphism with susceptibility to inflammatory bowel disease (IBD) in a Zhuang population from Guangxi, China.
METHODS: A case-control study was conducted from August 2009 to October 2012, which included intestinal tissue samples of 73 Zhuang and 67 Han unrelated IBD patients and 70 Zhuang and 78 Han unrelated healthy volunteers in Guangxi. Genomic DNA was extracted from intestinal tissue using the phenol-chloroform method. The rs10761659 locus of the 10q21 gene was amplified by polymerase chain reaction (PCR), genotyped by restriction fragment length polymorphism (RFLP) and verified by gene sequencing.
RESULTS: The homozygous mutant, heterozygous mutant and wild-type genotypes of the rs10761659 locus were found in both IBD patients and healthy controls, but the distribution of genotypes and allele frequencies was not significantly different among Crohn's disease, ulcerative colitis and control groups (P > 0.05). No significant difference was detected in the 10q21 gene rs10761659 polymorphism between Zhuang and Han patients with Crohn's disease or ulcerative colitis (P > 0.05).
CONCLUSION: The rs10761659 polymorphism of the 10q21 gene is not associated with susceptibility to IBD in the Zhuang population in Guangxi.
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Maus B, Jung C, Mahachie John JM, Hugot JP, Génin E, Van Steen K. Molecular reclassification of Crohn's disease: a cautionary note on population stratification. PLoS One 2013; 8:e77720. [PMID: 24147066 PMCID: PMC3798408 DOI: 10.1371/journal.pone.0077720] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 08/30/2013] [Indexed: 02/02/2023] Open
Abstract
Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn's disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic susceptibility to Crohn's disease is widely acknowledged and has been demonstrated by identification of over 100 CD associated genetic loci. However, relating CD subphenotypes to disease susceptible loci has proven to be a difficult task. In this paper we discuss the use of cluster analysis on genetic markers to identify genetic-based subgroups while taking into account possible confounding by population stratification. We show that it is highly relevant to consider the confounding nature of population stratification in order to avoid that detected clusters are strongly related to population groups instead of disease-specific groups. Therefore, we explain the use of principal components to correct for population stratification while clustering affected individuals into genetic-based subgroups. The principal components are obtained using 30 ancestry informative markers (AIM), and the first two PCs are determined to discriminate between continental origins of the affected individuals. Genotypes on 51 CD associated single nucleotide polymorphisms (SNPs) are used to perform latent class analysis, hierarchical and Partitioning Around Medoids (PAM) cluster analysis within a sample of affected individuals with and without the use of principal components to adjust for population stratification. It is seen that without correction for population stratification clusters seem to be influenced by population stratification while with correction clusters are unrelated to continental origin of individuals.
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Affiliation(s)
- Bärbel Maus
- UMR843, INSERM, Paris, France
- Bioinformatics and Modeling, GIGA-R, University of Liège, Liège, Belgium
| | - Camille Jung
- UMR843, Institut National de la Sante et de la recherche Medicale, Paris, France
- Service de Gastroentérologie Pédiatrique, Hôpital Robert Debré, APHP, Paris, France
- CRC-CRB, CHI Creteil, Creteil, France
| | - Jestinah M. Mahachie John
- UMR843, INSERM, Paris, France
- Bioinformatics and Modeling, GIGA-R, University of Liège, Liège, Belgium
| | - Jean-Pierre Hugot
- UMR843, Institut National de la Sante et de la recherche Medicale, Paris, France
- Service de Gastroentérologie Pédiatrique, Hôpital Robert Debré, APHP, Paris, France
- Labex Inflamex, Université Paris Diderot, Paris, France
| | - Emmanuelle Génin
- UMR1078, Génétique, Génomique fonctionnelle et Biotechnologies, INSERM, Brest, France
- Centre Hospitalier Régional Universitaire de Brest, Brest, France
| | - Kristel Van Steen
- UMR843, INSERM, Paris, France
- Bioinformatics and Modeling, GIGA-R, University of Liège, Liège, Belgium
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Associations between PTPN2 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. Inflamm Res 2013; 63:71-9. [PMID: 24127071 DOI: 10.1007/s00011-013-0673-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/29/2013] [Accepted: 10/03/2013] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Ulcerative colitis (UC) and Crohn's disease (CD) result from an interaction between genetic and environmental factors. Though several polymorphisms have been identified in PTPN2, their roles in the incidence of UC and CD are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk. METHOD PubMed, EMBASE, Cochrane Library and CBM were searched until 23 July 2013 for eligible studies on three PTPN2 polymorphisms: rs2542151, rs1893217 and rs7234029. Data were extracted, and pooled odd ratios (ORs) as well as 95 % confidence intervals (95 % CIs) were calculated. CONCLUSION The meta-analysis indicated that rs2542151, rs1893217 and rs1893217 were associated with increased CD risk, while the former was associated with increased UC risk. The differences in age of onset and ethnic groups may influence the associations. Gene-gene and gene-environment interactions should be investigated in the future. RESULTS Seventeen studies with 18,308 cases and 20,406 controls were included. Significant associations were found between rs2542151 polymorphism and CD susceptibility (OR = 1.22, 95 % CI, 1.15-1.30, I (2) = 32 %), as well as between rs2542151 and UC susceptibility (OR = 1.16, 95 % CI, 1.07-1.25, I (2) = 39 %). A similar result was found in Caucasians, but not in Asians. Moreover, a significant increase in CD risk for all carriers of the minor allele of rs1893217 (OR = 1.45, 95 % CI, 1.23-1.70, I (2) = 0 %) and rs7234029 (OR = 1.36, 95 % CI, 1.16-1.59, I (2) = 0 %) were found. For children, the rs1893217 polymorphism appeared to confer susceptibility to CD (OR = 1.56, 95 % CI, 1.28-1.89, I (2) = 0 %).
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Abstract
PURPOSE OF REVIEW The inflammatory bowel diseases (IBDs) are chronic disabling conditions. Despite the benefits of anti-tumor necrosis factor (TNF)-α agents in improving quality of life and reducing the need for surgeries, overall only one-third of patients are in clinical remission at 1 year and loss of response is frequent. It seems clear that treatment must go beyond alleviation of symptoms in IBD. It is important that treatment targets in IBD will ensure mucosal healing and deep remission. RECENT FINDINGS The induction of deep remission might be the best way to alter the natural course of these diseases by preventing disability and bowel damage. New disability indices and the new Crohn's disease damage score have recently been developed and they can be used to evaluate the long-term effect on patients and as new endpoints in trials. Early intervention with disease-modifying anti-IBD drugs (DMAIDs) should be considered in patients with poor prognostic factors. SUMMARY New therapeutic targets in IBD patients who failed anti-TNF-α therapy are urgently required, and tofacitinib, vedolizumab and ustekinumab appear to be the most promising drugs. Herein, we review the new and current trends in IBD therapy, with the final aim of changing disease course and patients' lives by both improving quality of life and avoiding disability.
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