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1
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van der Werf J, Fleming NI. Are single nucleotide polymorphisms underutilized for guiding treatment of inflammatory bowel disease? Immunol Cell Biol 2025. [PMID: 40313162 DOI: 10.1111/imcb.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 04/15/2025] [Accepted: 04/18/2025] [Indexed: 05/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU), significantly impacts quality of life. Despite significant advances in the management of the conditions, responses to treatments vary greatly, and this is due partly to our natural genetic variation. Here we will review the evidence for whether single nucleotide polymorphisms (SNPs) have the potential to guide treatment decisions for people with IBD. We will first consider SNPs that exhibit strong associations with IBD pathogenesis and their relevance to epithelial barrier integrity, cytokine production, and immune system function. Then, we will cover those SNPs implicated in altering response to our various current IBD therapeutics, including the recently implemented drugs ustekinumab and tofacitinib. Finally, we will explore lesser-known SNPs that exhibit complex relationships with the disease and which may be undervalued as pharmacogenetic tools. Overall, it will be demonstrated that SNPs associated with IBD pathology are largely distinct from those predicting response to treatments and that new discoveries of clinically useful tools can be expected from therapy-focused investigations. Given the growing list of treatments available, we argue that beneficial personalization of treatments based on SNPs is still underutilized.
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Affiliation(s)
| | - Nicholas Ian Fleming
- Department of Pathology, University of Otago, Dunedin, New Zealand
- The Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
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2
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Peruhova M, Stoyanova D, Miteva DG, Kitanova M, Mirchev MB, Velikova T. Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease. World J Exp Med 2025; 15:97404. [PMID: 40115750 PMCID: PMC11718585 DOI: 10.5493/wjem.v15.i1.97404] [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] [Received: 05/30/2024] [Revised: 10/09/2024] [Accepted: 11/14/2024] [Indexed: 12/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, Burgas 1000, Bulgaria
| | - Daniela Stoyanova
- Department of Gastroenterology, Military Medical Academy, Sofia 1606, Bulgaria
| | | | - Meglena Kitanova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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3
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Ballesta-López O, Gil-Candel M, Centelles-Oria M, Megías-Vericat JE, Solana-Altabella A, Ribes-Artero H, Nos-Mateu P, García-Pellicer J, Poveda-Andrés JL. Pharmacogenetics in Response to Biological Agents in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci 2025; 26:1760. [PMID: 40004223 PMCID: PMC11855474 DOI: 10.3390/ijms26041760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/07/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by microbial, environmental, genetic, and immune factors. The introduction of biological agents has transformed IBD therapy, improving symptoms, reducing complications, and enhancing patients' quality of life. However, approximately 30% of patients exhibit primary non-response, and 50% experience a loss of response over time. Genetic and non-genetic factors contribute to variability in treatment outcomes. This systematic review aims to thoroughly analyze and assess existing studies exploring the relationships between genetic variations and individual responses to biologic drugs, in order to identify genetic markers that are predictive of treatment efficacy, risk of adverse effects, or drug toxicity, thereby informing clinical practice and guiding future research. PubMed and EMBASE papers were reviewed by three independent reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] guidelines. Of the 883 records screened, 99 met the inclusion criteria. The findings of this review represent an initial step toward personalized medicine in IBD, with the potential to improve clinical outcomes in biological therapy.
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Affiliation(s)
- Octavio Ballesta-López
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Mayte Gil-Candel
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - María Centelles-Oria
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Juan Eduardo Megías-Vericat
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Antonio Solana-Altabella
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Accredited Research Group on Hematology, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Hugo Ribes-Artero
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Pilar Nos-Mateu
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Javier García-Pellicer
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - José Luis Poveda-Andrés
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Management Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
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4
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Kayali S, Fantasia S, Gaiani F, Cavallaro LG, de’Angelis GL, Laghi L. NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 2025; 31:552-562. [PMID: 38582044 PMCID: PMC11808579 DOI: 10.1093/ibd/izae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Indexed: 04/08/2024]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.
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Affiliation(s)
- Stefano Kayali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Stefano Fantasia
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy
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5
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Wang LF, Chen PR, He SK, Duan SH, Zhang Y. Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review. World J Gastroenterol 2023; 29:4481-4498. [PMID: 37621757 PMCID: PMC10445007 DOI: 10.3748/wjg.v29.i29.4481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/02/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.
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Affiliation(s)
- Liang-Fang Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ping-Run Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Ke He
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Hao Duan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Zhang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
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6
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Walia J, Mujahid R. Clinical Disease States Related to Mutations of the NOD2 Gene: A Case Report and Literature Review. Cureus 2023; 15:e38584. [PMID: 37288206 PMCID: PMC10243228 DOI: 10.7759/cureus.38584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2023] [Indexed: 06/09/2023] Open
Abstract
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a protein encoded by the NOD2 gene and plays an important role in the immune system. NOD2 is an intracellular pattern recognition receptor (PRR) responsible for the recognition of pathogens as well as the activation of many biochemical processes within cells of the host immune system. Mutations of the NOD2 gene can significantly impact the host's immune response against a variety of pathogens. In addition to immunodeficiency, mutations of the NOD2 gene have also been linked with several atopic diseases and autoimmune conditions such as rheumatoid arthritis and Crohn's disease (CD). There is also a distinct set of autoinflammatory conditions that are now classified as NOD2-associated autoinflammatory diseases (NAID). We present a case of a 63-year-old female with common variable immunodeficiency, eosinophilic asthma, and rheumatoid arthritis who was found to have a NOD2 mutation on genetic testing. As genetic testing continues to gain popularity, several disease states that were previously thought to be unrelated are now being recognized as originating from a common genetic defect.
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Affiliation(s)
- Jasmit Walia
- Internal Medicine, St. Luke's University Hospital - Bethlehem Campus, Bethlehem, USA
| | - Rehan Mujahid
- Allergy Immunology, St. Luke's University Hospital - Bethlehem Campus, Bethlehem, USA
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7
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Giri R, Hoedt EC, Khushi S, Salim AA, Bergot AS, Schreiber V, Thomas R, McGuckin MA, Florin TH, Morrison M, Capon RJ, Ó Cuív P, Begun J. Secreted NF-κB suppressive microbial metabolites modulate gut inflammation. Cell Rep 2022; 39:110646. [PMID: 35417687 DOI: 10.1016/j.celrep.2022.110646] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 01/24/2022] [Accepted: 03/16/2022] [Indexed: 12/27/2022] Open
Abstract
Emerging evidence suggests that microbiome-host crosstalk regulates intestinal immune activity and predisposition to inflammatory bowel disease (IBD). NF-κB is a master regulator of immune function and a validated target for the treatment of IBD. Here, we identify five Clostridium strains that suppress immune-mediated NF-κB activation in epithelial cell lines, PBMCs, and gut epithelial organoids from healthy human subjects and patients with IBD. Cell-free culture supernatant from Clostridium bolteae AHG0001 strain, but not the reference C. bolteae BAA-613 strain, suppresses inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from Winnie mice. The in vivo responses to Clostridium bolteae AHG0001 and BAA-613 mirror the in vitro activity. Thus, using our in vitro screening of bacteria capable of suppressing NF-κB in the context of IBD and using an ex vivo organoid-based approach, we identify a strain capable of alleviating colitis in a relevant pre-clinical animal model of IBD.
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Affiliation(s)
- Rabina Giri
- Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; Faculty of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Emily C Hoedt
- Faculty of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia; The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Shamsunnahar Khushi
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Angela A Salim
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Anne-Sophie Bergot
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Veronika Schreiber
- Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Ranjeny Thomas
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Michael A McGuckin
- Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; Faculty of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Timothy H Florin
- Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Mark Morrison
- Faculty of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia; The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Robert J Capon
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Páraic Ó Cuív
- Faculty of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia; The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia.
| | - Jakob Begun
- Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; Faculty of Medicine, The University of Queensland, St. Lucia, QLD 4072, Australia.
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8
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Alijani E, Naderi M, Mollashahi B, Atabaki M. Association between NOD2 gene polymorphisms and susceptibility to pulmonary tuberculosis in Zahedan, Southeast Iran. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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9
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Lan Y, Zhao E, Zhang X, Zhu X, Wan L, A S, Ping Y, Wang Y. Prognostic impact of a lymphocyte activation-associated gene signature in GBM based on transcriptome analysis. PeerJ 2021; 9:e12070. [PMID: 34527446 PMCID: PMC8401751 DOI: 10.7717/peerj.12070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/05/2021] [Indexed: 01/11/2023] Open
Abstract
Background Glioblastoma multiforme (GBM) is a highly, malignant tumor of the primary central nervous system. Patients diagnosed with this type of tumor have a poor prognosis. Lymphocyte activation plays important roles in the development of cancers and its therapeutic treatments. Objective We sought to identify an efficient lymphocyte activation-associated gene signature that could predict the progression and prognosis of GBM. Methods We used univariate Cox proportional hazards regression and stepwise regression algorithm to develop a lymphocyte activation-associated gene signature in the training dataset (TCGA, n = 525). Then, the signature was validated in two datasets, including GSE16011 (n = 150) and GSE13041 (n = 191) using the Kaplan Meier method. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors. Results We identified a lymphocyte activation-associated gene signature (TCF3, IGFBP2, TYRO3 and NOD2) in the training dataset and classified the patients into high-risk and low-risk groups with significant differences in overall survival (median survival 15.33 months vs 12.57 months, HR = 1.55, 95% CI [1.28-1.87], log-rank test P < 0.001). This signature showed similar prognostic values in the other two datasets. Further, univariate and multivariate Cox proportional hazards regression models analysis indicated that the signature was an independent prognostic factor for GBM patients. Moreover, we determined that there were differences in lymphocyte activity between the high- and low-risk groups of GBM patients among all datasets. Furthermore, the lymphocyte activation-associated gene signature could significantly predict the survival of patients with certain features, including IDH-wildtype patients and patients undergoing radiotherapy. In addition, the signature may also improve the prognostic power of age. Conclusions In summary, our results suggested that the lymphocyte activation-associated gene signature is a promising factor for the survival of patients, which is helpful for the prognosis of GBM patients.
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Affiliation(s)
- Yujia Lan
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Erjie Zhao
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Xinxin Zhang
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Xiaojing Zhu
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Linyun Wan
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Suru A
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Yanyan Ping
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
| | - Yihan Wang
- Harbin Medical University, College of Bioinformatics Science and Technology, Harbin, China
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10
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Dalal RS, Ananthakrishnan AN, Hamilton MJ, Winter RW. Two Strikes but Not Out: Deep Remission of Ulcerative Colitis with Ustekinumab After Primary Non-response to Infliximab and Vedolizumab. Dig Dis Sci 2021; 66:733-737. [PMID: 33569666 DOI: 10.1007/s10620-021-06852-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/12/2021] [Indexed: 12/20/2022]
Affiliation(s)
- Rahul S Dalal
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Crohn's and Colitis Center, Brigham and Women's Hospital, Boston, MA, 02467, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Matthew J Hamilton
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Crohn's and Colitis Center, Brigham and Women's Hospital, Boston, MA, 02467, USA
| | - Rachel W Winter
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA. .,Crohn's and Colitis Center, Brigham and Women's Hospital, Boston, MA, 02467, USA.
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11
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Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10040853. [PMID: 33669579 PMCID: PMC7922976 DOI: 10.3390/jcm10040853] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.
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12
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Mahajna H, Ben-Horin S. Novel bio-genetic predictors of response to biologic treatment in inflammatory bowel diseases. Curr Opin Pharmacol 2020; 55:132-140. [PMID: 33249396 DOI: 10.1016/j.coph.2020.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 02/07/2023]
Abstract
Despite the evolving therapeutic armamentarium, the treatment of IBD patients remains challenging and many patients fail to respond to biologic agents. With the limited yield of clinical factors to predict the outcome of biologic treatments, studies have focused on identifying genetic alterations and circulating or tissue biomarkers to identify patients who are likely to respond to therapy. In this review, we examine the current knowledge and status of genetic, expression biomarkers, and microbiome predictors. The search for genetic predictors has yielded many genetic loci variants, but few were reproducible. Expression studies of putative biomarkers show promising results, especially with TREM1, oncostatin M and TNF biomarkers, but confirmatory studies are warranted. Finally, the microbiome is emerging as an important player with specific taxa and functional pathways differentially abundant and enriched in responders versus non-responders to certain biologics. Integrating different factors into a robust predictive model, which is both reproducible, accurate and affordable, remains the main challenge before these individualized strategies can reach clinical use.
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Affiliation(s)
- Hussein Mahajna
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel.
| | - Shomron Ben-Horin
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel
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13
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Ahn MY, Kang JK, Kwon SM, Yoon HE, Yoon JH. Expression of nucleotide-binding oligomerization domain 1 and 2 in oral lichen planus. J Dent Sci 2020; 15:1-8. [PMID: 32256993 PMCID: PMC7109494 DOI: 10.1016/j.jds.2019.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 11/28/2019] [Indexed: 11/16/2022] Open
Abstract
Background/purpose Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa. The present study investigated the expression of nucleotide-binding oligomerization domain (NOD), a pivotal sensor protein of the innate immune system, in OLP. Materials and methods Oral mucosal biopsies were collected from 20 patients with OLP and 6 individuals with normal oral mucosa (NOM). The expression of NOD1 and NOD2 was determined using RT-PCR and immunohistochemistry in OLP and NOM samples. Results The mRNA expression of NOD1 and NOD2 was significantly higher in the OLP group than in the NOM group. The protein expression of NOD1 was marginally upregulated in all mucosal layers in the OLP group compared with that of the NOM group; however, the differences were not significant. The expression of NOD2 was elevated in infiltrating lymphocytes of the submucosal layer in the OLP group compared with the NOM group, but was undetected in other inflammatory disease, inflammatory fibrous hyperplasia (IFH). This study revealed the upregulation of NOD2 mRNA and protein in the OLP group, but not in the NOM group. Conclusion These findings suggest that NOD2 may play an important role in the pathogenesis of OLP and represents a new diagnostic and treatment target.
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Affiliation(s)
- Mee-Young Ahn
- Major in Pharmaceutical Engineering, Division of Bio-industry, College of Medical and Life Sciences, Silla University, Busan, Republic of Korea
| | - Jin-Kyu Kang
- Department of Oral Medicine and Orofacial Pain, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon, Republic of Korea
| | - Seong-Min Kwon
- Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Daejeon Dental Hospital, Wonkwang University, Daejeon, Republic of Korea
| | - Hyo-Eun Yoon
- Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Daejeon Dental Hospital, Wonkwang University, Daejeon, Republic of Korea
| | - Jung-Hoon Yoon
- Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Daejeon Dental Hospital, Wonkwang University, Daejeon, Republic of Korea
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14
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Wang MH, Friton JJ, Raffals LE, Leighton JA, Pasha SF, Picco MF, Cushing KC, Monroe K, Nix BD, Newberry RD, Faubion WA. Novel Genetic Risk Variants Can Predict Anti-TNF Agent Response in Patients With Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:1036-1043. [PMID: 30689765 PMCID: PMC7185197 DOI: 10.1093/ecco-jcc/jjz017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/16/2018] [Accepted: 01/20/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND It is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD. MATERIALS AND METHODS Mayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy. RESULTS Of 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23). CONCLUSIONS Novel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.
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Affiliation(s)
- Ming-Hsi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA,Corresponding author: Ming-Hsi Wang, MD, PhD, Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. Tel.: 904-953-6970; fax: 904-953-6225;
| | - Jessica J Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan A Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Shabana F Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Michael F Picco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Kelly C Cushing
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA,Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - Kelly Monroe
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - Billy D Nix
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - Rodney D Newberry
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - William A Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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15
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Gole B, Potočnik U. Pre-Treatment Biomarkers of Anti-Tumour Necrosis Factor Therapy Response in Crohn's Disease-A Systematic Review and Gene Ontology Analysis. Cells 2019; 8:cells8060515. [PMID: 31141991 PMCID: PMC6628089 DOI: 10.3390/cells8060515] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/24/2019] [Accepted: 05/25/2019] [Indexed: 12/15/2022] Open
Abstract
The most prominent treatment for the serious cases of Crohn’s disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be of great value. Clinical predictors have, however, proved insufficient. Here, we integrate genomic and expression data on potential pre-treatment biomarkers of anti-TNF nonresponse. We show that there is almost no overlap between genomic (annotated with tissue-specific expression quantitative trait loci data) and transcription (RNA and protein data) biomarkers. Furthermore, using interaction networks we demonstrate there is little direct interaction between the proposed biomarkers, though a majority do have common interactors connecting them into networks. Our gene ontology analysis shows that these networks have roles in apoptotic signalling, response to oxidative stress and inflammation pathways. We conclude that a more systematic approach with genome-wide search of genomic and expression biomarkers in the same patients is needed in future studies.
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Affiliation(s)
- Boris Gole
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia.
| | - Uroš Potočnik
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia.
- Laboratory for Biochemistry, Molecular biology and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
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16
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Yao Q, Li E, Shen B. Autoinflammatory disease with focus on NOD2-associated disease in the era of genomic medicine. Autoimmunity 2019; 52:48-56. [PMID: 31084224 DOI: 10.1080/08916934.2019.1613382] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Systemic autoinflammatory diseases (SAIDs) represent a spectrum of genetically heterogeneous inflammatory disorders. Some SAID-associated genes are located in chromosome 16, including familial Mediterranean fever gene (MEFV) and nucleotide-binding oligomerization domain 2 [NOD2] gene that are linked to Crohn's disease, Blau syndrome, and Yao syndrome. These disorders share overlapping clinical phenotypes, and genotyping is diagnostically helpful and distinctive. Using next generation sequencing in SAIDs, digenic variants or combinations of more genetic variants in different genes can be detected, and they may be related to the MEFV and NOD2 genes. These variants may contribute to heterogeneous phenotypes in an individual, complicating the diagnosis and therapy. An awareness of the clinical significance of the digenic or combined gene variants is important in the era of genomic medicine.
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Affiliation(s)
- Qingping Yao
- a Division of Rheumatology, Allergy and Immunology , Stony Brook University , Stony Brook , NY , USA
| | - Ellen Li
- b Division of Gastroenterology , Stony Brook University , Stony Brook , NY , USA
| | - Bo Shen
- c Center for Inflammatory Bowel Disease , Digestive Disease and Surgery Institute, the Cleveland Clinic Foundation , Cleveland , OH , USA
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17
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Hooper KM, Barlow PG, Henderson P, Stevens C. Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:661-671. [PMID: 30590697 DOI: 10.1093/ibd/izy380] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. The etiology involves a combination of genetic and environmental factors resulting in abnormal immune responses to intestinal microbiota. Genetic studies have strongly linked genes involved in autophagy to CD, and genes involved in the unfolded protein response (UPR) to IBD. The UPR is triggered in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), and autophagy plays a key role in relieving ER stress and restoring homeostasis. This review summarizes the known interactions between autophagy and the UPR and discusses the impact of these converging pathways on IBD pathogenesis. With a paucity of effective long-term treatments for IBD, targeting of synergistic pathways may provide novel and more effective therapeutic options.
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Affiliation(s)
- Kirsty M Hooper
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
| | - Peter G Barlow
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
| | - Paul Henderson
- Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
| | - Craig Stevens
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
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18
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The role of the NOD2/CARD15 gene in surgical treatment prediction in patients with Crohn's disease. Int J Colorectal Dis 2019; 34:347-351. [PMID: 30069743 DOI: 10.1007/s00384-018-3122-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/05/2018] [Indexed: 02/04/2023]
Abstract
PURPOSE Crohn's disease (CD) belongs to chronic disorders with unpredictable disease course. The aim of this study was to identify how genetic testing (NOD2/CARD15) can be used in patients with CD to predict the need for surgical treatment (to define an aggressive type of disease where the patient can profit from early surgery). METHODS The patients who were tested genetically had undergone a surgery due to CD at the Department of Surgery University Hospital Brno Bohunice between 2010 and 2016. The control group consisted of patients with CD who had been diagnosed with CD at least 5 years prior to the testing and had not required any surgical intervention. The second control group was healthy subjects. RESULTS In total, there were 117 operated patients for CD, 77 patients with CD that had not undergone surgery for CD and 30 healthy subjects. For patients with at least one genetic mutation, the risk of the necessity of surgical treatment of CD is 1.96 times higher than for patients with no mutation. Patients with two or more mutations were generally operated on at a younger age, in a shorter time after being diagnosed and each patient had a partial resection of the ileum. CONCLUSION The group of operated patients with CD had a significantly higher distribution of at least one genetic mutation as opposed to the non-operated group. In patients with two or more mutations, the disease course was more aggressive. This group of patients might profit from the conservative top-down or early surgical therapy.
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19
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Besnard V, Calender A, Bouvry D, Pacheco Y, Chapelon-Abric C, Jeny F, Nunes H, Planès C, Valeyre D. G908R NOD2 variant in a family with sarcoidosis. Respir Res 2018; 19:44. [PMID: 29554915 PMCID: PMC5859391 DOI: 10.1186/s12931-018-0748-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 03/13/2018] [Indexed: 12/16/2022] Open
Abstract
Background Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis. Methods Sarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis. Results In the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions. Conclusions Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages. Electronic supplementary material The online version of this article (10.1186/s12931-018-0748-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Valérie Besnard
- Université Paris 13, Sorbonne Paris Cité, Laboratoire EA2363 "Hypoxie et Poumon", 74 rue Marcel Cachin, 93017, Bobigny cedex, France.
| | - Alain Calender
- Génétique des cancers et maladies multifactorielles, Hospices Civils de Lyon, GHE, Centre de Biologie et Pathologie ES, Bron, France
| | - Diane Bouvry
- Université Paris 13, Sorbonne Paris Cité, Laboratoire EA2363 "Hypoxie et Poumon", 74 rue Marcel Cachin, 93017, Bobigny cedex, France.,AP-HP, Hôpital Avicenne, Bobigny, France
| | - Yves Pacheco
- Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Université Claude Bernard - Lyon 1, EA-7426, Lyon, France.,Université Claude Bernard Lyon 1 - EA-7426, 165 Chemin du Grand Revoyet, F-69495, Pierre Benite, France
| | - Catherine Chapelon-Abric
- Department of Internal Medicine and Clinical Immunology, Groupe Hospitalier La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Florence Jeny
- Université Paris 13, Sorbonne Paris Cité, Laboratoire EA2363 "Hypoxie et Poumon", 74 rue Marcel Cachin, 93017, Bobigny cedex, France.,AP-HP, Hôpital Avicenne, Bobigny, France
| | - Hilario Nunes
- Université Paris 13, Sorbonne Paris Cité, Laboratoire EA2363 "Hypoxie et Poumon", 74 rue Marcel Cachin, 93017, Bobigny cedex, France.,AP-HP, Hôpital Avicenne, Bobigny, France
| | - Carole Planès
- Université Paris 13, Sorbonne Paris Cité, Laboratoire EA2363 "Hypoxie et Poumon", 74 rue Marcel Cachin, 93017, Bobigny cedex, France.,AP-HP, Hôpital Avicenne, Bobigny, France
| | - Dominique Valeyre
- Université Paris 13, Sorbonne Paris Cité, Laboratoire EA2363 "Hypoxie et Poumon", 74 rue Marcel Cachin, 93017, Bobigny cedex, France.,AP-HP, Hôpital Avicenne, Bobigny, France
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20
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Abstract
Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD.
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Affiliation(s)
- Ming-Hsi Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
| | - Michael F Picco
- Department of Gastroenterology and Hepatology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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21
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Abstract
Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.
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Affiliation(s)
- Kirsty M Hooper
- School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Peter G Barlow
- School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Craig Stevens
- School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Paul Henderson
- Child Life and Health, University of Edinburgh, Edinburgh, UK
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK
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22
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Barber GE, Yajnik V, Khalili H, Giallourakis C, Garber J, Xavier R, Ananthakrishnan AN. Genetic Markers Predict Primary Non-Response and Durable Response To Anti-TNF Biologic Therapies in Crohn's Disease. Am J Gastroenterol 2016; 111:1816-1822. [PMID: 27596696 PMCID: PMC5143156 DOI: 10.1038/ajg.2016.408] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/03/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. METHODS From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. RESULTS From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10-12). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10-13). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. CONCLUSIONS Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.
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Affiliation(s)
- Grant E Barber
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Vijay Yajnik
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Cosmas Giallourakis
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - John Garber
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Ramnik Xavier
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
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23
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Wang X, Qin L, Cao J, Zhao J. Impact of NOD2/CARD15 polymorphisms on response to monoclonal antibody therapy in Crohn's disease: a systematic review and meta-analysis. Curr Med Res Opin 2016; 32:2007-2012. [PMID: 27533749 DOI: 10.1080/03007995.2016.1226168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Crohn's disease (CD) is frequently treated with anti-tumor necrosis factor (TNF)α monoclonal antibodies, and NOD2/CARD15 polymorphisms have been reported to predict treatment response. The purpose of this study was to perform a meta-analysis to determine the effect of NOD2/CARD15 polymorphisms on treatment response in patients with CD. METHODS Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 December 2015 using the keywords: NOD2, CARD15, polymorphism, Crohn's disease. Randomized controlled trials, prospective, retrospective, and cohort studies of patients with CD who received NOD2/CARD15 genetic analysis and were treated with monoclonal antibodies were included. The primary outcome was treatment response. RESULTS Of 104 records identified, only four studies were relevant and included in the analysis. The four studies included 355 patients with CD, patient age ranged from 35 to 41 years, and the proportion of males ranged from 33% to 38%; however, only two studies reported age and sex data. Patients were treated with adalimumab and/or infliximab. Analysis revealed that NOD2/CARD15 mutations were not significantly associated with response to adalimumab or infliximab treatment (pooled odds ratio [OR] = 1.35, 95% confidence interval [CI]: 0.78 to 2.32, p = .278). CONCLUSIONS NOD2/CARD15 polymorphisms do not predict response to adalimumab and infliximab in patients with CD. However, the number of included studies was small and treatment protocols varied. Further studies are necessary to determine the role of NOD2/CARD15 polymorphisms in patients with CD.
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Affiliation(s)
- Xiaolei Wang
- a Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - Li Qin
- b Tongji University School of Medicine , Shanghai , China
| | - Jingli Cao
- b Tongji University School of Medicine , Shanghai , China
| | - Jing Zhao
- b Tongji University School of Medicine , Shanghai , China
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24
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Abstract
Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data.
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25
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Jakobsen C, Cleynen I, Andersen PS, Vermeire S, Munkholm P, Paerregaard A, Wewer V. Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease. J Crohns Colitis 2014; 8:678-85. [PMID: 24394805 DOI: 10.1016/j.crohns.2013.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 11/28/2013] [Accepted: 12/15/2013] [Indexed: 02/06/2023]
Abstract
AIM To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS In this case-control study we included IBD patients <18 years of age at diagnosis from the Danish National Patient Registry and healthy children <18 years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1-1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1-1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5-0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers.
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Affiliation(s)
- C Jakobsen
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark.
| | - I Cleynen
- Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - P S Andersen
- Department of Microbiology and Infection Control, State Serum Institute, Copenhagen, Denmark
| | - S Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Belgium
| | - P Munkholm
- Department of Gastroenterology, Medical Section, Herlev University Hospital, Copenhagen, Denmark
| | - A Paerregaard
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark
| | - V Wewer
- Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark
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26
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Freire P, Cardoso R, Figueiredo P, Donato MM, Ferreira M, Mendes S, Ferreira AM, Vasconcelos H, Portela F, Sofia C. NOD2 gene mutations in ulcerative colitis: useless or misunderstood? Int J Colorectal Dis 2014; 29:653-61. [PMID: 24651958 DOI: 10.1007/s00384-014-1850-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/09/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE NOD2 mutations have been linked to an increased risk of Crohn's disease and to some of its phenotypes. The association between NOD2 mutations and susceptibility to ulcerative colitis (UC) remains somewhat controversial and potential correlations between these mutations and UC phenotype have not been studied. AIM To assess whether NOD2 mutations are a risk factor for UC in Portugal and if there are any genotype-phenotype correlations in these patients. METHODS The three main NOD2 mutations were searched in 200 patients with UC and in 202 healthy controls. RESULTS NOD2 mutations were present in 28 patients with UC (14.0 %) and in 27 controls (13.4 %) (p = 0.853). Mutation carriers were more likely to receive steroids during the first year of disease than non-carriers (54.2 % vs. 29.6 %, p = 0.018) and among these patients the need for intravenous administration was more frequent in those with the R702W polymorphism (90.0 % vs. 45.5 %, p = 0.014). In patients with severe colitis admitted for intravenous steroids, a greater proportion of mutation carriers was considered intravenous-steroid refractory and required salvage therapy (90.0 % vs. 38.1 %, p = 0.004). Patients with NOD2 mutation were submitted to colectomy more frequently than non-carriers (17.9 % vs. 4.1 %. p = 0.015). No correlation with the need for immunosuppressants/immunomodulators was found. CONCLUSIONS In the Portuguese population, NOD2 mutations do not increase the risk of UC but are associated with a more aggressive course including greater need of steroids in the first year, increased incidence of intravenous-steroid refractoriness and a higher colectomy rate.
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Affiliation(s)
- Paulo Freire
- Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Avenida Bissaya Barreto, 3000, Coimbra, Portugal,
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Thomas D, Gazouli M, Karantanos T, Rigoglou S, Karamanolis G, Bramis K, Zografos G, Theodoropoulos GE. Association of rs1568885, rs1813443 and rs4411591 polymorphisms with anti-TNF medication response in Greek patients with Crohn's disease. World J Gastroenterol 2014; 20:3609-3614. [PMID: 24707144 PMCID: PMC3974528 DOI: 10.3748/wjg.v20.i13.3609] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 12/23/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the correlation between rs1568885, rs1813443 and rs4411591 polymorphisms and response to infliximab in a cohort of Greek patients with Crohn's disease (CD). METHODS One hundred and twenty-six patients diagnosed with CD based on standard clinical, endoscopic, radiological, and pathological criteria were enrolled in this study at the Gastroenterology Unit of the 2(nd) Department of Surgery and at the Colorectal Unit of the 1st Department of Propaedeutic Surgery. Infliximab at a dose of 5 mg/kg was administered intravenously at weeks 0, 2, 6 and then every 8 wk. Clinical and serological responses were assessed using the Harvey-Bradshaw Index and serum C-reactive protein (CRP) levels, respectively, and the endoscopic response was evaluated by ileocolonoscopy performed at baseline and after 12-20 wk of therapy. The changes in endoscopic appearance compared to baseline were classified into four categories, and patients were classified as responders and non-responders. Genomic DNA from whole peripheral blood was extracted and genotyping was performed by allele-specific polymerase chain reactions. χ (2) test with Yate's correction based on the S-Plus was used to compare the genotype frequencies. RESULTS Eighty patients (63.49%) were classified as complete and 32 (25.39%) as partial responders to infliximab, while 14 (11.11%) were primary non-responders. No correlation was found between response to infliximab and patients' characteristics such as age, gender and disease duration. There was consistency between Harvey-Bradshaw index scores and serum CRP levels. The TT genotype of the rs1568885 polymorphism was significantly related to partial response (P = 0.024) and resistance to infliximab (P = 0.007) while the AT genotype was more frequent in partial responders (P = 0.035) and in primary non-responders (P = 0.032). Regarding rs1813443, the CC genotype was found to be associated with partial response (P = 0.005) and primary resistance (P = 0.002) to infliximab while no association was found between the rs4411591 polymorphism and the clinical response to infliximab. CONCLUSION Based on our results, the rs1568885 and rs1813443 polymorphisms are associated with clinical and biochemical response to infliximab in Greek patients with Crohn's disease.
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St-Pierre J, Chadee K. How the discovery of TNF-α has advanced gastrointestinal diseases and treatment regimes. Dig Dis Sci 2014; 59:712-5. [PMID: 24504593 DOI: 10.1007/s10620-014-3042-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Joëlle St-Pierre
- Department of Microbiology, Immunology and Infectious Diseases, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada,
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Posovszky C, Pfalzer V, Lahr G, Niess JH, Klaus J, Mayer B, Debatin KM, von Boyen GBT. Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease. BMC Gastroenterol 2013; 13:77. [PMID: 23635032 PMCID: PMC3659055 DOI: 10.1186/1471-230x-13-77] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 04/26/2013] [Indexed: 02/08/2023] Open
Abstract
Background Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD). Methods 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). Results Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). Conclusions These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.
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Affiliation(s)
- Carsten Posovszky
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr, 24, Ulm, 89075, Germany.
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Abstract
NOD1 {nucleotide-binding oligomerization domain 1; NLRC [NOD-LRR (leucine-rich repeat) family with CARD (caspase recruitment domain) 1]} and NOD2 (NLRC2) are among the most prominent members of the NLR (NOD-LRR) family –proteins that contain nucleotide-binding NACHT domains and receptor-like LRR domains. With over 20 members identified in humans, NLRs represent important components of the mammalian innate immune system, serving as intracellular receptors for pathogens and for endogenous molecules elaborated by tissue injury. NOD1 and NOD2 proteins operate as microbial sensors through the recognition of specific PG (peptidoglycan) constituents of bacteria. Upon activation, these NLR family members initiate signal transduction mechanisms that include stimulation of NF-κB (nuclear factor-κB), stress kinases, IRFs (interferon regulatory factors) and autophagy. Hereditary polymorphisms in the genes encoding NOD1 and NOD2 have been associated with an increasing number of chronic inflammatory diseases. In fact, potential roles for NOD1 and NOD2 in inflammatory disorders have been revealed by investigations using a series of animal models. In the present review, we describe recent experimental findings associating NOD1 and NOD2 with various autoimmune and chronic inflammatory disorders, and we discuss prospects for development of novel therapeutics targeting these NLR family proteins.
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