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Bezzio C, Cavalli CAM, Franchellucci G, Dal Buono A, Gabbiadini R, Scalvini D, Manara S, Narcisi A, Armuzzi A, Saibeni S. Psoriasis and inflammatory bowel disease: concomitant IMID or paradoxical therapeutic effect? A scoping review on anti-IL-12/23 and anti-IL-23 antibodies. Therap Adv Gastroenterol 2024; 17:17562848241299564. [PMID: 39575159 PMCID: PMC11580083 DOI: 10.1177/17562848241299564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/18/2024] [Indexed: 11/24/2024] Open
Abstract
Inflammatory bowel diseases (IBD) and psoriasis are chronic inflammatory conditions belonging to the heterogeneous group of immune-mediated inflammatory diseases (IMIDs). A significant bidirectional link between these two entities has been observed, conditioning an increased risk of IBD in patients with psoriasis and vice-versa. Biological therapies used for IBD may lead to the occurrence of psoriasis as a "paradoxical reaction." The objective of this study is to analyze the current evidence on the association between psoriasis and IBD, particularly finding case reports of the appearance or aggravation of psoriasis under therapy with interleukin-12/23 (IL-12/23) and IL-23 inhibitors. We conducted comprehensive research to identify studies examining the association between psoriasis and IBD and to find case presentations that reported the appearance or aggravation of psoriasis under biologic therapy with IL-12/23 and IL-23 inhibitors up to March 2024. Clinical trials for IL-12/23 and IL-23 inhibitors in IBD were analyzed to find cases of paradoxical psoriasis as registered adverse events. The sources of evidence are PubMed and ClinicalTrials.gov. For each included case report, data on patient characteristics concerning their age, sex, and comorbidities were selected. Moreover, information regarding the indication for biologic therapy, time to onset of paradoxical psoriasis after starting treatment, clinical presentation, and management of the paradoxical psoriasis was extracted. We found 10 reported cases of ustekinumab-induced new-onset or worsening psoriasis and one reported case of paradoxical psoriasis induced by risankizumab in the literature. Four cases of paradoxical psoriasis have been also registered in clinical trials involving ustekinumab treatment in IBD. Psoriasis can constitute a rare paradoxical adverse event of ustekinumab treatment, but further studies are needed to better clarify the cytokine imbalance that leads to this phenomenon induced by inhibition of IL-12/23 and IL-23. Still, few real-world data exist to draw any conclusions, but risankizumab may positively treat psoriasis induced by ustekinumab.
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Affiliation(s)
- Cristina Bezzio
- IBD Centre, IRCCS Humanitas, Research Hospital, Rozzano, Lombardia 20089, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Carolina Aliai Micol Cavalli
- Gastroenterology and Digestive Endoscopy Unit, Santa Maria degli Angeli Hospital, Azienda Sanitaria Friuli Occidentale, Pordenone, Italy
| | | | - Arianna Dal Buono
- IBD Centre, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | | | - Davide Scalvini
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Sofia Manara
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | | | - Alessandro Armuzzi
- IBD Centre, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Simone Saibeni
- IBD Centre, Gastroenterology Unit, Rho Hospital, ASST Rhodense, Rho, Italy
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Williams PT. Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets. PeerJ 2021; 9:e10914. [PMID: 33628645 PMCID: PMC7894107 DOI: 10.7717/peerj.10914] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND "Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities (h 2) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown. METHODS Serum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (βFS, h 2 ={(1 + 8rspouseβFS)0.5 - 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h 2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples. RESULTS Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring's age- and sex-adjusted CRP distribution when estimated from βOP (P trend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from βFS (P trend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile. CONCLUSION Heritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF-α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.
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Affiliation(s)
- Paul T. Williams
- Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
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Small heat shock protein CRYAB inhibits intestinal mucosal inflammatory responses and protects barrier integrity through suppressing IKKβ activity. Mucosal Immunol 2019; 12:1291-1303. [PMID: 31481750 DOI: 10.1038/s41385-019-0198-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 08/03/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Alpha B-crystallin (CRYAB) is an important member of the small heat shock protein family, and plays a protective and therapeutic role in neurological inflammation. CRYAB expression was assessed in cultured HT29 and Caco-2 cells and inflamed mucosa of patients with inflammatory bowel disease (IBD) and colitis models in mice. Lentivirus-overexpressing and CRSIPR/Cas9 systems were used in different cells to upregulate and silence CRYAB expression, respectively. Cell permeable recombined fusion protein TAT-CRYAB was injected intraperitoneally into dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice to assess its anti-inflammatory effects. CRYAB was found to be significantly decreased in the inflamed mucosa from IBD patients and DSS-induced colitis in mice, and negatively correlated with the levels of TNF-α and IL-6, respectively. Enforced expression of CRYAB suppressed expression of proinflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, and IL-8) via inhibiting the IKK complex formation, whereas lack of CRYAB expression markedly enhanced proinflammatory responses. Consistently, administration of TAT-CRYAB fusion protein significantly alleviated DSS- or TNBS-induced colitis in mice and protected intestinal barrier integrity. CRYAB regulates inflammatory response in intestinal mucosa by inhibiting IKKβ-mediated signaling and may serve as a novel therapeutic approach in the treatment of IBD.
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Iwamoto T, Yashima K, Morio K, Ueda N, Ikebuchi Y, Kawaguchi K, Harada K, Isomoto H. Association of Clinical Features with Human Leukocyte Antigen in Japanese Patients with Ulcerative Colitis. Yonago Acta Med 2018. [DOI: 10.33160/yam.2018.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Taku Iwamoto
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kazuo Yashima
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Keiko Morio
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Naoki Ueda
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Yuichiro Ikebuchi
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
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López-Posadas R, Neurath MF, Atreya I. Molecular pathways driving disease-specific alterations of intestinal epithelial cells. Cell Mol Life Sci 2017; 74:803-826. [PMID: 27624395 PMCID: PMC11107577 DOI: 10.1007/s00018-016-2363-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/06/2016] [Accepted: 09/08/2016] [Indexed: 12/22/2022]
Abstract
Due to the fact that chronic inflammation as well as tumorigenesis in the gut is crucially impacted by the fate of intestinal epithelial cells, our article provides a comprehensive overview of the composition, function, regulation and homeostasis of the gut epithelium. In particular, we focus on those aspects which were found to be altered in the context of inflammatory bowel diseases or colorectal cancer and also discuss potential molecular targets for a disease-specific therapeutic intervention.
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Affiliation(s)
- Rocío López-Posadas
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany.
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Cytokine production by PBMC and serum from allergic and non-allergic subjects following in vitro histamine stimulation to test fexofenadine and osthole anti-allergic properties. Eur J Pharmacol 2016; 791:763-772. [PMID: 27756601 DOI: 10.1016/j.ejphar.2016.10.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/14/2016] [Accepted: 10/14/2016] [Indexed: 11/21/2022]
Abstract
FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. This paper compares peripheral blood mononuclear cell (PBMC) incubation with FXF and osthole, by studying FXF, osthole and histamine cytokine secretion in PBMC in vitro cultures. Mabtech kits determined the interleukins IL-1β, IL-4, IL-10, IL-13 and TNF-α. The influence of the above active substances on cytokine secretion in PBMC's and serum was assessed: cytokines were IL-1β, IL-4, IL-10, IL-13 and TNF-α; and cytokine levels secreted by untreated PBMCs in pure culture medium formed the absolute control (ctrl). We determined that osthole affects PBMC cytokine secretion to almost precisely the same extent as FXF (IL-1β, IL-4, IL-10 and TNF). In addition osthole had greater IL-13 blocking ability than FXF. Moreover, we observed significantly decreased IL-4 level in histamine/osthole theatment compared to histamine alone. Meanwhile, FXF not significantly decrease the level of IL-4 increased by histamine. This data indicates osthole's strong role in allergic inflamation. All results confirm our hypothesis that osthole is a natural histamine antagonist and therefore can be beneficially used in antihistamine treatment of conditions such as allergies.
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Vlachos C, Gaitanis G, Katsanos KH, Christodoulou DK, Tsianos E, Bassukas ID. Psoriasis and inflammatory bowel disease: links and risks. PSORIASIS-TARGETS AND THERAPY 2016; 6:73-92. [PMID: 29387596 PMCID: PMC5683131 DOI: 10.2147/ptt.s85194] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Psoriasis and the spectrum of inflammatory bowel diseases (IBD) are chronic, inflammatory, organotropic conditions. The epidemiologic coexistence of these diseases is corroborated by findings at the level of disease, biogeography, and intrafamilial and intrapatient coincidence. The identification of shared susceptibility loci and DNA polymorphisms has confirmed this correlation at a genetic level. The pathogenesis of both diseases implicates the innate and adaptive segments of the immune system. Increased permeability of the epidermal barrier in skin and intestine underlies the augmented interaction of allergens and pathogens with inflammatory receptors of immune cells. The immune response between psoriasis and IBD is similar and comprises phagocytic, dendritic, and natural killer cell, along with a milieu of cytokines and antimicrobial peptides that stimulate T-cells. The interplay between dendritic cells and Th17 cells appears to be the core dysregulated immune pathway in all these conditions. The distinct similarities in the pathogenesis are also reflected in the wide overlapping of their therapeutic approaches. Small-molecule pharmacologic immunomodulators have been applied, and more recently, biologic treatments that target proinflammatory interleukins have been introduced or are currently being evaluated. However, the fact that some treatments are quite selective for either skin or gut conditions also highlights their crucial pathophysiologic differences. In the present review, a comprehensive comparison of risk factors, pathogenesis links, and therapeutic strategies for psoriasis and IBD is presented. Specific emphasis is placed on the role of the immune cell species and inflammatory mediators participating in the pathogenesis of these diseases.
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Affiliation(s)
| | | | - Konstantinos H Katsanos
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Dimitrios K Christodoulou
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Epameinondas Tsianos
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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Abstract
Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, and racial and ethnic differences in disease prevalence. Recently, several new genes have been identified to be involved in the genetic susceptibility to IBD. The characterization of novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD. The development of genetic markers associated with clinical outcomes in patients with IBD will be very important in the future. The progress of molecular biology tools (microarrays, proteomics, and epigenetics) have progressed the field of the genetic markers discovery. The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve, characterize, and analyze large amounts of data generated by the technological advances. The techniques available for markers development are genomics (single nucleotide polymorphism genotyping, pharmacogenetics, and gene expression analyses) and proteomics. This could be a potential great benefit in predicting the course of disease in individual patients and in guiding appropriate medical therapy.
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Zhu S, Li J, Bing Y, Yan W, Zhu Y, Xia B, Chen M. Diet-Induced Hyperhomocysteinaemia Increases Intestinal Inflammation in an Animal Model of Colitis. J Crohns Colitis 2015; 9:708-19. [PMID: 26071411 DOI: 10.1093/ecco-jcc/jjv094] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 05/22/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hyperhomocysteinaemia [HHcy] is a common phenomenon observed in patients with inflammatory bowel disease [IBD]. Homocysteine is a pro-inflammatory molecule and has been identified as a risk factor for cardiovascular and cerebral diseases. Whether HHcy contributes to the chronic inflammation of the colon in IBD has rarely been explored. The aim of this study was to investigate the effect of HHcy on dextran sulphate sodium [DSS]-induced colitis. METHODS Wistar rats were randomly divided into eight groups: [1] Control; [2] HHcy; [3] p38 inhibitor; [4] DSS; [5] HHcy + DSS; [6] HHcy + DSS+p38 inhibitor; [7] HHcy + DSS [21 days]; and [8] HHcy + DSS + folate [21 days]. Colitis was induced by 5% DSS. HHcy was induced by the normal rodent diet containing 1.7% methionine. The mRNA expression of interleukin 17 [IL-17] was detected by qRT-PCR. The protein expressions of IL-17, retinoid-related orphan nuclear receptor-γt [RORγt], p38 MAPK, phosphorylated-p38 MAPK, cytosolic phospolipaseA2 [cPLA2], phosphorylated-cPLA2, and cyclooxygenase 2 [COX2] were detected by immunoblot analysis. RESULTS The rats of the HHcy + DSS group had significantly higher myeloperoxidase [MPO] activity, DAI score, and histological score. HHcy significantly increased the plasma concentration, the colonic mRNA, and the protein levels of IL-17. HHcy also activated p38 MAPK and cPLA2, and increased the protein levels of COX2 and RORγt as well as the plasma level of prostaglandin E2 [PGE2]. Folate supplementation down-regulated homocysteine-induced IL-17 and RORγt expressions. CONCLUSIONS HHcy aggravated DSS-induced colitis by stimulating IL-17 expression via the p38/cPLA2/COX2/PGE2 signalling pathway. The folate supplementation may represent a novel approach to treating the chronic intestinal inflammation of IBD exacerbated by HHcy.
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Affiliation(s)
- Siying Zhu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Jin Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Yuntao Bing
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Wenfeng Yan
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Youqing Zhu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Bing Xia
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
| | - Min Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China
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Singh K, Prasad KN, Mishra P, Singh SK, Kharwar NK, Prasad N, Gupta A, Srivastava JK. Association of tumour necrosis factor-α polymorphism in patients with end stage renal disease. Nephrology (Carlton) 2015; 20:387-91. [DOI: 10.1111/nep.12398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2015] [Indexed: 12/13/2022]
Affiliation(s)
- Kamini Singh
- Department of Microbiology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
- Amity Institute of Biotechnology; Amity University; Lucknow India
| | - Kashi Nath Prasad
- Department of Microbiology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Priyanka Mishra
- Department of Microbiology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Satyendra Kumar Singh
- Department of Microbiology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Nagendra Kumar Kharwar
- Department of Microbiology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Narayan Prasad
- Department of Nephrology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Amit Gupta
- Department of Nephrology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
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Vacuolar protein sorting 4B regulates apoptosis of intestinal epithelial cells via p38 MAPK in Crohn's disease. Exp Mol Pathol 2015; 98:55-64. [DOI: 10.1016/j.yexmp.2014.12.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 12/18/2014] [Indexed: 01/16/2023]
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Yang L, Yan Y. Protein kinases are potential targets to treat inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2014; 5:209-217. [PMID: 25374761 PMCID: PMC4218950 DOI: 10.4292/wjgpt.v5.i4.209] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 04/05/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Protein kinases play a crucial role in the pathogenesis of inflammatory bowel disease (IBD), the two main forms of which are ulcerative colitis and Crohn’s disease. In this article, we will review the mechanisms of involvement of protein kinases in the pathogenesis of and intervention against IBD, in terms of their effects on genetics, microbiota, mucous layer and tight junction, and the potential of protein kinases as therapeutic targets against IBD.
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Günther C, Buchen B, Neurath MF, Becker C. Regulation and pathophysiological role of epithelial turnover in the gut. Semin Cell Dev Biol 2014; 35:40-50. [DOI: 10.1016/j.semcdb.2014.06.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 06/02/2014] [Indexed: 12/25/2022]
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Regeling A, Somasundaram R, de Haar C, van der Woude CJ, Braat H, Peppelenbosch MP. Role of defective autophagia and the intestinal flora in Crohn disease. SELF NONSELF 2014; 1:323-327. [PMID: 21487507 DOI: 10.4161/self.1.4.13990] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The precise mechanisms underlying the development of Crohn disease (CD) remain controversial, but sufficient data have been collected to suggest that an uncontrolled immune response within the intestinal mucosa leads to inflammation in a genetically susceptible host. Although lack of mucosal regulatory T cells causes colitis in humans and experimental rodents, patients with CD have more rather than less regulatory activity in the intestine, apparently excluding defects in tolerance as the cause of CD. Genome-wide association studies have identified many gene variants that confer susceptibility and which seem associated to diminished functioning of especially innate immunity. In apparent agreement, CD patients are impaired with respect to innate immune responses and controlling bacterial flora in the intestine. Furthermore, severe genetic deficiencies in innate immunity, like e.g., lack of NADP oxidase activity or diminished function of the Wiskott Aldrich syndrome protein are associated with colitis in mice and men, and are often mistakenly diagnosed as CD. Thus we favor the view that the primary defect in CD is a lack in innate immunity, causing second tier immunological defenses to combat otherwise easily controlled bacterial breaches of the mucosal barrier.
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Affiliation(s)
- Anouk Regeling
- Diseases University Medical Center Groningen Hanzeplein 1 9713 GZ Groningen, The Netherlands
| | - Rajesh Somasundaram
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - Colin de Haar
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - Henri Braat
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
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Sarlos P, Kovesdi E, Magyari L, Banfai Z, Szabo A, Javorhazy A, Melegh B. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature. World J Gastrointest Pathophysiol 2014; 5:304-21. [PMID: 25133031 PMCID: PMC4133528 DOI: 10.4291/wjgp.v5.i3.304] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/19/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.
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Bonyadi M, Abdolmohammadi R, Jahanafrooz Z, Somy MH, Khoshbaten M. TNF-alpha gene polymorphisms in Iranian Azari Turkish patients with inflammatory bowel diseases. Saudi J Gastroenterol 2014; 20:108-12. [PMID: 24705148 PMCID: PMC3987150 DOI: 10.4103/1319-3767.129475] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
CONTEXT Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the bowel (IBD) whose causes are not fully known. Emerging data indicate that alterations in cytokine synthesis may play a role in IBD pathogenesis. AIMS We aimed to determine the association between tumor necrosis factor-alfa (TNFα) promoter polymorphisms (at positions - 308 and - 1031) and susceptibility to IBD among Iranian Azari Turkish patients. SETTINGS AND DESIGN One hundred and one patients with IBD and 100 healthy subjects were analyzed. MATERIALS AND METHODS Both polymorphisms in the promoter region of the TNFα gene at positions -1031T/C and -308G/A were detected by polymerase chain reaction-restriction fragment length polymorphism assay. All statistical analyses were calculated with SPSS for Windows 16.0. The Fisher's exact test was used to test for departure from Hardy-Weinberg equilibrium of the genotype frequencies (P > 0.05). RESULTS The allele frequency of the TNFα-308G and -1031T were higher in IBD patients but did not reach statistical significance. However, the homozygous TT genotype for the SNP-1031 T > C was significantly higher in UC patients than in healthy controls (P = 0.01) and the heterozygous CT genotype for the SNP -1031 T > C was significantly lower in UC patients than in healthy controls (P = 0.03). CONCLUSIONS The TNFα-1031 T allele confers a significant risk for developing UC in Iranian Azeri Turkish patients. Also the frequency of TNFα-1031 C allele was considerably low among patients with UC and it may have protective role among them (OR = 0.43; P = 0.01).
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Affiliation(s)
- Mortaza Bonyadi
- Liver and Gastrointestinal Disease Research Centre of Tabriz University of Medical Sciences, Tabriz, Iran,Address for correspondence: Dr. Mortaza Bonyadi, Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran. E-mail:
| | - Reza Abdolmohammadi
- Liver and Gastrointestinal Disease Research Centre of Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Jahanafrooz
- Department of Genetics, Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad-Hosein Somy
- Liver and Gastrointestinal Disease Research Centre of Tabriz University of Medical Sciences, Tabriz, Iran
| | - Manoochehr Khoshbaten
- Liver and Gastrointestinal Disease Research Centre of Tabriz University of Medical Sciences, Tabriz, Iran
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Günther C, Neumann H, Neurath MF, Becker C. Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut 2013; 62:1062-71. [PMID: 22689519 DOI: 10.1136/gutjnl-2011-301364] [Citation(s) in RCA: 346] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Intestinal epithelial cells (IEC) are organised as a single cell layer which covers the intestine. Their primary task is to absorb nutrients present in the intestinal lumen. However, IEC also play an important role in the immune defence of our body by building a barrier that separates the bowel wall from potentially hazardous bacteria present in the gut lumen. The life cycle of IEC is determined by the time span in which cells migrate from their place of origin at the crypt base to the villus tip, from where they are shed into the lumen. Cell death in the intestinal epithelium has to be tightly regulated and irregularities might cause pathologies. Excessive cell death has been associated with chronic inflammation as seen in patients with Crohn's disease and ulcerative colitis. While until recently apoptosis was discussed as being essential for epithelial turnover and tissue homeostasis in the intestinal epithelium, recent data using gene deficient mice have challenged this concept. Moreover, an apoptosis-independent mode of programmed cell death, termed necroptosis, has been identified and described in the intestinal epithelium. The following article reviews previous studies on cell death regulation in IEC and a potential role of necroptosis for gut homeostasis.
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Affiliation(s)
- Claudia Günther
- Department of Medicine, University of Erlangen-Nuremberg, Hartmannstrasse 14, 91 054 Erlangen, Germany
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18
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Roff AN, Panganiban RP, Bond JS, Ishmael FT. Post-transcriptional regulation of meprin α by the RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP). J Biol Chem 2012; 288:4733-43. [PMID: 23269677 DOI: 10.1074/jbc.m112.444208] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Meprins are multimeric proteases that are implicated in inflammatory bowel disease by both genetic association studies and functional studies in knock-out mice. Patients with inflammatory bowel disease show decreased colonic expression of meprin α, although regulation of expression, particularly under inflammatory stimuli, has not been studied. The studies herein demonstrate that the human meprin α transcript is bound and stabilized by Hu antigen R at baseline, and that treatment with the inflammatory stimulus phorbol 12-myristate 13-acetate downregulates meprin α expression by inducing tristetraprolin. The enhanced binding of tristetraprolin to the MEP1A 3'-UTR results in destabilization of the transcript and occurs at a discrete site from Hu antigen R. This is the first report to describe a mechanism for post-transcriptional regulation of meprin α and will help clarify the role of meprins in the inflammatory response and disease.
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Affiliation(s)
- Alanna N Roff
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
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19
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A common haplotype of carnitine palmitoyltransferase 1b is associated with the metabolic syndrome. Br J Nutr 2012; 109:810-5. [PMID: 22809552 DOI: 10.1017/s0007114512002656] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into mitochondria to provide substrates for β-oxidation. We performed an analysis including three coding SNP in the muscle isoform of the CPT1b gene (rs3213445, rs2269383 and rs470117) and one coding SNP in the CPT2 gene (rs1799821) to find associations with traits of the metabolic syndrome (MetS). Male participants (n 755) from the Metabolic Intervention Cohort Kiel were genotyped and phenotyped for features of the MetS. Participants underwent a glucose tolerance test and a postprandial assessment of metabolic variables after a standardised mixed meal. Carriers of the rare CPT1b 66V (rs3213445) allele had significantly higher γ-glutamyl transpeptidase (GGT), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvate transaminase (GPT) activities (P< 0·0001, P= 0·03 and P= 0·048, respectively) and a higher fatty liver index (FLI, P= 0·026). Fasting and postprandial TAG (P= 0·007 and P= 0·009, respectively) and fasting glucose (P= 0·012) were significantly higher in 66V-allele carriers. The insulin sensitivity index determined after a glucose load was lower in those subjects (P= 0·005). Total cholesterol (P= 0·051) and LDL-cholesterol (P= 0·062) tended to be higher in 66V-allele carriers when compared with I66I homozygotes. Homozygosity of the rare K531E allele presented with lower GGT and GOT activities (P= 0·011 and P= 0·027, respectively). E531E homozygotes tended to have lower GPT and FLI (P= 0·078 and P= 0·052, respectively). CPT2 V368I (rs1799821) genotypic groups did not differ in the investigated anthropometric and metabolic parameters. The present results confirm the association of CPT1b coding polymorphisms with the MetS, with a deleterious effect of the CPT1b I66V and a protective impact of the CPT1b K531E SNP, whereas haplotype analysis indicates a relevance of the E531K polymorphism only.
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20
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Yu JI, Kang IH, Seo GS, Choi SC, Yun KJ, Chae SC. Promoter polymorphism of the EED gene is associated with the susceptibility to ulcerative colitis. Dig Dis Sci 2012; 57:1537-1543. [PMID: 22271413 DOI: 10.1007/s10620-012-2045-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 01/05/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND Embryonic ectoderm development (EED) protein is involved in multiple cellular protein complexes. EED mediates the repression of gene activity through histone deacetylation, and it may act as a specific regulator of integrin's function. This gene was identified as a candidate gene for the susceptibility to IBD by our previous cDNA microarray analysis. AIM The present study aimed to validate the expression level of the EED gene in patients with IBD by performing RT-PCR, and we investigated whether the polymorphisms in the EED gene are associated with the susceptibility to UC, and whether a functional EED promoter polymorphism is related to UC. METHODS Genotype analysis of the EED SNPs was performed by single-base extension analysis. The haplotype frequencies of the EED gene for multiple loci were estimated using the expectation maximization algorithm. The promoter region of the human EED gene, including the g.-1850G>C allele, was isolated by PCR. The amplified PCR products were inserted into the pGL3-basic vector and the luciferase activity was analyzed. RESULTS The expression level of the EED gene was significantly decreased in both the UC and CD patients and it was significantly higher in the liver and ileum than in the other tissues of the human digestive system. The genotype and allele frequencies of the g.-1850G>C polymorphism of the EED gene in the UC patients were significantly different from those of the healthy controls (p = 0.018 and 0.017, respectively). The luciferase activity assay showed that the promoter activity was decreased about twofold in the construct containing the g.-1850G allele compared to that of the construct containing the g.-1850C allele, which means that the allele G could produce less EED mRNA. CONCLUSIONS These results suggest that the g.-1850G>C polymorphism in the EED gene might be associated with the susceptibility to UC by the change of the EED expression level.
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Affiliation(s)
- Ji-In Yu
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, South Korea
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21
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Achkar JP, Klei L, de Bakker PI, Bellone G, Rebert N, Scott R, Lu Y, Regueiro M, Brzezinski A, Kamboh MI, Fiocchi C, Devlin B, Trucco M, Ringquist S, Roeder K, Duerr RH. Amino acid position 11 of HLA-DRβ1 is a major determinant of chromosome 6p association with ulcerative colitis. Genes Immun 2012; 13:245-52. [PMID: 22170232 PMCID: PMC3341846 DOI: 10.1038/gene.2011.79] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Revised: 10/12/2011] [Accepted: 10/31/2011] [Indexed: 01/25/2023]
Abstract
The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRβ1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRβ1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.
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Affiliation(s)
- Jean-Paul Achkar
- Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Lambertus Klei
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Paul I.W. de Bakker
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Julius Center for Health Sciences and Primary Care, and Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gaia Bellone
- Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania
| | - Nancy Rebert
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Regan Scott
- Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ying Lu
- Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
| | - Miguel Regueiro
- Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Aaron Brzezinski
- Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
| | - M. Ilyas Kamboh
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Claudio Fiocchi
- Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Massimo Trucco
- Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
| | - Steven Ringquist
- Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
| | - Kathryn Roeder
- Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania
- Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
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22
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The effect of FABP2 promoter haplotype on response to a diet with medium-chain triacylglycerols. GENES AND NUTRITION 2012; 7:437-45. [PMID: 22270906 DOI: 10.1007/s12263-012-0280-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 01/03/2012] [Indexed: 12/28/2022]
Abstract
The fatty-acid-binding protein-2 (FABP2) gene has been proposed as a candidate gene for diabetes because the encoded protein is involved in fatty acid absorption and therefore may affect insulin sensitivity and glucose metabolism. The rare haplotype (B) of its promoter was shown to be associated with a lower risk for type 2 diabetes. The aim of this study was to investigate whether a polymorphism in the FABP2 promoter does affect the metabolic response to either an medium-chain triacylglycerol (MCT) or an long-chain triacylglycerol (LCT) diet, which were suggested to differ in transport mechanisms, in affinity to FABP2, in activating transcription factors binding to the FABP2 promoter and in their effects on insulin sensitivity. We studied 82 healthy male subjects varying in the FABP2 promoter (42 homozygous for common haplotype (A), 40 homozygous for the rare haplotype (B)) in an interventional study with either an MCT or LCT diet over 2 weeks to examine gene-nutrient interaction. The saturation grade of MCT was adjusted to that of the LCT fat. We determined glucose, insulin, triacylglycerols (TGs), chylomicron triacylglycerols and cholesterol before and after a standardised mixed meal before and after the intervention. HDL cholesterol increased in all groups, which was most pronounced in subjects homozygous for the common promoter haplotype A who received MCT diet (P = 0.001), but not significant in homozygous rare haplotype B subjects who received MCT fat. Subjects homozygous for FABP2 haplotype A showed a significant decrease in fasting and postprandial glucose (P = 0.01, 0.04, respectively) and a decrease in insulin resistance (HOMA-IR, P = 0.04) during LCT diet. After correction for multiple testing, those effects did not remain significant. Fasting and postprandial triacylglycerols, LDL cholesterol, chylomicron TGs and cholesterol were not affected by genotype or diet. MCT diet increased HDL cholesterol dependent on the FABP2 promoter haplotype. The effects of the promoter haplotype B could be mediated by PPARγ, which is upregulated by medium-chain fatty acids.
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Abstract
Tumour necrosis factor (TNF), an important proinflammatory cytokine, plays a role in the regulation of cell differentiation, proliferation and death, as well as in inflammation, innate and adaptive immune responses, and also implicated in a wide variety of human diseases. The presence of DNA sequence variations in regulatory region might interfere with transcription of TNF gene, influencing the circulating level of TNF and thus increases the susceptibility to human diseases (infectious, cancer, autoimmune, neurodegenerative and other diseases). In this review, we have comprehensively analysed various published case-control studies of different types of human diseases, in which TNF gene polymorphism played a role, and computationally predicted several single nucleotide polymorphisms (SNPs) lie in transcription factor-binding sites (TFBS) of transcription factors (TFs). It has been observed that TNF enhancer polymorphism is implicated in several diseases, and TNF rs1800629 and rs361525 SNPs are the most important in human disease susceptibility as these might influence the transcription of TNF gene. Thirty-two SNPs lies in TFBS of 20 TFs have been detected in the TNF upstream region. It has been found that TNF enhancer polymorphism influences the serum level of TNF in different human diseases and thus affects the susceptibility to diseases. The presence of DNA sequence variation in TNF gene causes the modification of transcriptional regulation and thus responsible for association of susceptibility/resistance with human diseases.
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Affiliation(s)
- T Qidwai
- Metabolic and Structural Biology Department, Central Institute of Medicinal and Aromatic Plants, Council of Scientific and Industrial Research, Lucknow, Uttar Pradesh, India
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24
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Siggers RH, Hackam DJ. The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases. Cell Mol Life Sci 2011; 68:3623-34. [PMID: 21986983 PMCID: PMC11114911 DOI: 10.1007/s00018-011-0821-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Revised: 09/07/2011] [Accepted: 09/07/2011] [Indexed: 12/31/2022]
Abstract
The maintenance of mucosal barrier equilibrium in the intestine requires a delicate and dynamic balance between enterocyte loss by apoptosis and the generation of new cells by proliferation from stem cell precursors at the base of the intestinal crypts. When the balance shifts towards either excessive or insufficient apoptosis, a broad range of gastrointestinal diseases can manifest. Recent work from a variety of laboratories has provided evidence in support of a role for receptors of the innate immune system, including Toll-like receptors 2, 4, and 9 as well as the intracellular pathogen recognition receptor NOD2/CARD15, in the initiation of enterocyte apoptosis. The subsequent induction of enterocyte apoptosis in response to the activation of these innate immune receptors plays a key role in the development of various intestinal diseases, including necrotizing enterocolitis, Crohn's disease, ulcerative colitis, and intestinal cancer. This review will detail the regulatory pathways that govern enterocyte apoptosis, and will explore the role of the innate immune system in the induction of enterocyte apoptosis in gastrointestinal disease.
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Affiliation(s)
- Richard H. Siggers
- Division of Pediatric Surgery, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224 USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - David J. Hackam
- Division of Pediatric Surgery, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224 USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA
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25
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A variant in the heart-specific fatty acid transport protein 6 is associated with lower fasting and postprandial TAG, blood pressure and left ventricular hypertrophy. Br J Nutr 2011; 107:1422-8. [PMID: 21920065 DOI: 10.1017/s0007114511004727] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Fatty acid transport protein 6 (FATP6) is primarily expressed in the heart and seems to be involved in cardiac fatty acid uptake. Therefore, we investigated whether a variation in the 5'-untranslated region of the FATP6 gene is associated with features of the metabolic syndrome and signs of myocardial alteration or heart failure. A total of 755 male participants from a Metabolic Intervention Cohort Kiel were genotyped for the FATP6-7T>A polymorphism (rs2526246) and phenotyped for features of the metabolic syndrome. Participants underwent a glucose tolerance test and the postprandial assessment of metabolic variables after a standardised mixed meal. Left ventricular heart function was evaluated in fifty-four participants. Fasting (P = 0·01) and postprandial (P = 0·02) TAG concentrations were significantly lower in AA homozygotes when compared with wild-type carriers. Homozygosity of allele A was associated with significantly lower postprandial insulin concentrations after a glucose load and significantly lower systolic (P = 0·01) and diastolic (P = 0·01) blood pressure values compared with wild-type carriers. Accordingly, left ventricular heart mass was significantly lower in twenty-seven AA homozygotes in comparison with twenty-seven TT homozygotes, matched for BMI (P = 0·04). In conclusion, the effects of the FATP6 polymorphism on TAG are mediated by affluent dietary fat. The FATP6-7T>A polymorphism may protect from traits of the metabolic syndrome and CVD.
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26
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Thompson AI, Lees CW. Genetics of ulcerative colitis. Inflamm Bowel Dis 2011; 17:831-48. [PMID: 21319274 DOI: 10.1002/ibd.21375] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2010] [Accepted: 05/10/2010] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4α, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics.
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Packwood K, Drewe E, Staples E, Webster D, Witte T, Litzman J, Egner W, Sargur R, Sewell W, Lopez-Granados E, Seneviratne SL, Powell RJ, Ferry BL, Chapel HM. NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders. Clin Exp Immunol 2011; 161:536-41. [PMID: 20646002 DOI: 10.1111/j.1365-2249.2010.04216.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.
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Affiliation(s)
- K Packwood
- Department of Immunology, Oxford Radcliffe Hospitals, Oxford, UK.
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Santana G, Bendicho MT, Santana TC, Reis LBD, Lemaire D, Lyra AC. The TNF-α -308 polymorphism may affect the severity of Crohn's disease. Clinics (Sao Paulo) 2011; 66:1373-8. [PMID: 21915486 PMCID: PMC3161214 DOI: 10.1590/s1807-59322011000800011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2011] [Accepted: 05/04/2011] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE The goal of this project was to analyze the association between Crohn's disease, its clinical features, and the tumor necrosis factor alpha (TNF-α) -308 polymorphism. METHODS This is a case-control and cross-sectional study that enrolled 91 patients with Crohn's disease and 91 controls. Patients with Crohn's disease were characterized according to the Montreal Classification, along with their clinical and surgical treatment history. Analysis of the TNF-α -308 polymorphism was performed using a commercial kit. A stratified analysis was applied using an OR (odds ratio) with a 95% confidence interval. The chi-square and Fisher's exact tests were utilized for analysis of the association between the polymorphism and the clinical features of Crohn's disease. RESULTS The low producer predicted phenotype was present in 76.9% of Crohn's disease cases and 75.8% of controls (OR 0.94 [0.45-1.97]). The TNF2 allele and the high producer predicted phenotype were more frequent among patients with Crohn's disease penetrating behavior (p = 0.004). The TNF2 allele and the high producer predicted phenotype were also associated with a history of colectomy (p = 0.02), and the TNF2 allele was associated with small bowel resection (p = 0.03). CONCLUSIONS The TNF-α -308 polymorphism appears to affect the severity of the disease. However, TNF-α -308 polymorphism does not appear to be important for the susceptibility in the development of Crohn's disease.
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Affiliation(s)
- Genoile Santana
- Federal University of Bahia/Prof. Edgard Santos University Hospital - Gastroenterology, Salvador/BA, Brazil.
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Rolhion N, Barnich N, Bringer MA, Glasser AL, Ranc J, Hébuterne X, Hofman P, Darfeuille-Michaud A. Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion. Gut 2010; 59:1355-62. [PMID: 20587550 PMCID: PMC2976078 DOI: 10.1136/gut.2010.207456] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Crohn's disease (CD) ileal lesions are colonised by pathogenic adherent-invasive Escherichia coli (AIEC) producing outer membrane vesicles (OMVs) that contribute to the bacterial invasion process. In addition, increased expression of endoplasmic reticulum (ER)-localised stress response proteins, due to ER stress, is observed in patients with CD. The expression of the ER-localised stress response protein Gp96 in patients with CD and its biological role with regards to the ability of AIEC to invade intestinal epithelial cells were analysed. METHODS AND RESULTS Immunohistochemistry on tissue arrays showed that, together with CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6) or the ER stress protein Grp78, Gp96 is also strongly expressed at the apical plasma membrane of the ileal epithelial cells of 50% of patients with CD. Invasion experiments in the presence of antibodies raised against Gp96, or after transfection of Intestine-407 cells with gp96 small interfering RNA (siRNA), indicated that Gp96 is essential to promote AIEC LF82 invasion, allowing, via the recognition of the outer membrane protein OmpA, OMVs to fuse with intestinal epithelial cells. CONCLUSIONS Gp96 is overexpressed on the apical surface of ileal epithelial cells in patients with CD and acts as a host cell receptor for OMVs, promoting AIEC invasion. From the results shown here, it is speculated that AIEC could take advantage of the abnormal expression of Gp96 in patients with CD to invade the ileal mucosa.
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Affiliation(s)
- Nathalie Rolhion
- Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Nicolas Barnich
- Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | | | - Anne-Lise Glasser
- Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Julien Ranc
- Clermont Université, Université d'Auvergne, Clermont-Ferrand, France
| | - Xavier Hébuterne
- INSERM ERI-21/EA 4319, Laboratoire de Pathologie Clinique et Expérimentale et CRB INSERM, Hôpital Pasteur, et Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France
| | - Paul Hofman
- INSERM ERI-21/EA 4319, Laboratoire de Pathologie Clinique et Expérimentale et CRB INSERM, Hôpital Pasteur, et Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France
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Chae SC, Yu JI, Oh GJ, Choi CS, Choi SC, Yang YS, Yun KJ. Identification of single nucleotide polymorphisms in the TNFRSF17 gene and their association with gastrointestinal disorders. Mol Cells 2010; 29:21-28. [PMID: 20016944 DOI: 10.1007/s10059-010-0002-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2009] [Revised: 09/16/2009] [Accepted: 10/01/2009] [Indexed: 12/25/2022] Open
Abstract
TNFRSF17 is preferentially expressed in mature B lymphocytes, and may be important for the development of B cells. TNFRSF17 is selected as a candidate susceptibility gene to IBD pathogenesis by our cDNA microarray analysis, and we showed the specific expression of TNFRSF17 in resting and activated CD19(+) cells obtained from human blood. We identified four SNPs (g-1729G>A, g.2295T>C, g.2445G>A and g.2493G>A) and one variation site (g.894delT) in the TNFRSF17 gene using direct sequencing analysis. In addition, the association of the genotype and allelic frequencies of these SNPs was studied in healthy controls and in patients with ulcerative colitis (UC) or irritable bowel syndrome (IBS). Although, the genotype and allelic frequencies of these SNPs, in the UC and IBS patients, were not significantly different from those in the healthy controls, the distribution of the AAG, GGA, AGG and AAA haplotypes, of the SNPs (g.-1729G>A, g.2445G> A and g.2493G>A) associated with the TNFRSF17 gene, in the UC patients, were notably different from those of the healthy controls (P = 0.002, 0.002, 4.7E-4 and 3.3E-6, respectively). Moreover, the frequencies of the AAG, AGG, GAG and GAA haplotypes were significantly different in the IBS patients compared to the healthy controls (P = 4.2E-5, 4.4E-17, 1.8E-22 and 1.6E-10, respectively). These results suggest that the haplotypes of the TNFRSF17 polymorphisms might be associated with UC and IBS susceptibility.
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Affiliation(s)
- Soo-Cheon Chae
- Department of Pathology, Wonkwang University, Iksan, 570-749, Korea
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Abstract
X-box binding protein 1 (XBP1) is a unique basic region leucine zipper (bZIP) transcription factor whose active form is generated by a nonconventional splicing reaction upon disruption of homeostasis in the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR). XBP1, first identified as a key regulator of major histocompatibility complex (MHC) class II gene expression in B cells, represents the most conserved signaling component of UPR and is critical for cell fate determination in response to ER stress. Here we review recent advances in our understanding of this multifaceted transcription factor in health and diseases.
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Affiliation(s)
- Yin He
- *Graduate Program in Genetics and Development, Cornell University, Ithaca, NY, USA
| | - Shengyi Sun
- †Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY, USA
| | - Haibo Sha
- ‡Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Ziying Liu
- †Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY, USA
| | - Liu Yang
- †Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY, USA
| | - Zhen Xue
- §Graduate Program in Nutrition, Cornell University, Ithaca, NY, USA
| | - Hui Chen
- ‡Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Ling Qi
- *Graduate Program in Genetics and Development, Cornell University, Ithaca, NY, USA
- †Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY, USA
- ‡Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
- §Graduate Program in Nutrition, Cornell University, Ithaca, NY, USA
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Lees CW, Satsangi J. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol 2009; 3:513-34. [PMID: 19817673 DOI: 10.1586/egh.09.45] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Epidemiological data, detailed molecular studies and recent genome-wide association studies strongly suggest that ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic diseases that share some susceptibility loci, but differ at others. To date, there are more than 50 confirmed inflammatory bowel disease genes/loci, a number that is widely anticipated to at least double in the next 2 years. Germline variation in IL23R, IL12B, JAK2 and STAT3 is associated with inflammatory bowel disease susceptibility, consistent with the newly described role for IL23 signaling and Th17 cells in disease pathogenesis. Several genes involved in different aspects of bacterial handling are defective only in CD, including NOD2 and the autophagy genes ATG16L1 and IRGM. IL10 and ECM1 are associated with UC, while inherited variation at the HLA region is related to an inflammatory colonic phenotype. The application of genome-wide association studies to inflammatory bowel disease has been successful in defining the genetic architecture of CD and UC and in delivering genuinely novel and important insights into disease pathogenesis. This has unearthed a plethora of attractive targets for the development of future therapeutics. Insights into the natural history of these complex diseases will follow and may enable appropriate patient selection for early aggressive therapy with the view to modifying the disease course.
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Affiliation(s)
- Charlie W Lees
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
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Sanchez R, Levy E, Costea F, Sinnett D. IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn’s disease location. World J Gastroenterol 2009; 15:3776-82. [PMID: 19673019 PMCID: PMC2726456 DOI: 10.3748/wjg.15.3776] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [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 determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-α and the interleukin (IL)-10 in childhood Crohn’s disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes.
METHODS: Ten variants in GR, TNF-α and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin.
RESULTS: For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5’flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively.
CONCLUSION: This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.
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Ben Aleya W, Sfar I, Mouelhi L, Aouadi H, Makhlouf M, Ayed-Jendoubi S, Matri S, Filali A, Najjar T, Ben Abdallah T, Ayed K, Gorgi Y. Association of Fas/Apo1 gene promoter (-670 A/G) polymorphism in Tunisian patients with IBD. World J Gastroenterol 2009; 15:3643-8. [PMID: 19653342 PMCID: PMC2721238 DOI: 10.3748/wjg.15.3643] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [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 detect a possible association between the polymorphism of the (-670 A/G) Fas/Apo1 gene promoter and susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) in the Tunisian population.
METHODS: The (-670 A/G) Fas polymorphism was analyzed in 105 patients with CD, 59 patients with UC, and 100 controls using the polymerase chain reaction restriction fragment length polymorphism method.
RESULTS: Significantly lower frequencies of the Fas -670 A allele and A/A homozygous individuals were observed in CD and UC patients when compared with controls. Analysis of (-670 A/G) Fas polymorphism with respect to sex in CD and UC showed a significant difference in A/A genotypes between female patients and controls (P corrected = 0.004 in CD patients and P corrected = 0.02 in UC patients, respectively). Analysis also showed a statistically significant association between genotype AA of the (-670 A/G) polymorphism and the ileum localization of the lesions (P corrected = 0.048) and between genotype GG and the colon localization (P corrected = 0.009). The analysis of inflammatory bowel disease patients according to clinical behavior revealed no difference.
CONCLUSION: Fas-670 polymorphism was associated with the development of CD and UC in the Tunisian population.
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Abstract
The concept that genetic variation underlies inter-individual differences in drug response and contributes to the risk of developing common, complex disorders is expanding rapidly. Consequently the interest in genetic translational research has increased. Polymorphic DNA markers, either microsatellites or single nucleotide polymorphisms (SNPs), are used to assess genetic identities and track genetic differences between individuals. Given their abundance and stability, SNPs hold great promise as markers for mapping disease susceptibility loci for common, complex disorders by association studies. For this purpose the development of inexpensive, accurate, high-throughput methods for scoring large numbers of SNPs from hundreds of patients and controls is critical. Furthermore, gene expression profiling using DNA microarrays is likely to become a useful diagnostic tool enabling classification of disease phenotype based on molecular basis of disease pathogenesis, revealing information that cannot be obtained by histological assessment. Moreover, identification of differentially expressed genes in affected versus control tissue or over time in affected tissue will lead to better understanding of the mechanisms underlying disease and ultimately to the development of more effective drug therapies. To illustrate the potential of genetic translational research, several examples in the field of gastroenterology are described.
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Affiliation(s)
- J J M Ter Linde
- Dept. of Gastroenterology, University Medical Centre Utrecht, The Netherlands.
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Banerjee S, Oneda B, Yap LM, Jewell DP, Matters GL, Fitzpatrick LR, Seibold F, Sterchi EE, Ahmad T, Lottaz D, Bond JS. MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosal Immunol 2009; 2:220-31. [PMID: 19262505 PMCID: PMC2670347 DOI: 10.1038/mi.2009.3] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the alpha-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012-0.04), and one in the 3'-untranslated region (P=2 x 10(-7)) that displayed associations with UC. Moreover, meprin-alpha mRNA was decreased in inflamed mucosa of IBD patients. Meprin-alpha knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-alpha expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.
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Affiliation(s)
- S Banerjee
- Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - B Oneda
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - LM Yap
- Department of Gastroenterology, The Alfred, Melbourne, Victoria, Australia
| | - DP Jewell
- Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford, UK
| | - GL Matters
- Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - LR Fitzpatrick
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - F Seibold
- Department of Gastroenterology, University of Bern, Bern, Switzerland
| | - EE Sterchi
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - T Ahmad
- Department of Gastroenterology, Royal Devon and Exeter Hospital, Exeter, UK
| | - D Lottaz
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
- Department of Rheumatology, Clinical Immunology and Allergology, Inselspital, University of Bern, Bern, Switzerland
| | - JS Bond
- Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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Yoshida T, Kato K, Yokoi K, Watanabe S, Metoki N, Satoh K, Aoyagi Y, Nishigaki Y, Nozawa Y, Yamada Y. Association of candidate gene polymorphisms with chronic kidney disease in Japanese individuals with hypertension. Hypertens Res 2009; 32:411-8. [PMID: 19282863 DOI: 10.1038/hr.2009.22] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although hypertension has been recognized as a risk factor for chronic kidney disease (CKD), the genetic factors for predisposition to CKD in individuals with hypertension remain largely unknown. The purpose of this study was to identify the genetic variants that confer susceptibility to CKD among individuals with hypertension. The study population comprised 3696 Japanese individuals with hypertension (2265 men, 1431 women), including 1257 individuals (789 men, 468 women) with CKD (estimated glomerular filtration rate (eGFR) <60 ml min(-1) per 1.73 m(2)) and 2439 controls (1476 men, 963 women; eGFR >or=60 ml min(-1) per 1.73 m(2)). The genotypes for 30 polymorphisms of 26 candidate genes were determined. An initial screening of allele frequencies by the chi(2)-test revealed that eight polymorphisms were significantly (false discovery rate <0.05) associated with the prevalence of CKD in hypertensive individuals. Subsequent multivariable logistic regression analysis with adjustment for covariates as well as a stepwise forward selection procedure revealed that the T --> C (Val591Ala) polymorphism of APOB (rs679899), the -681C --> G polymorphism of PPARG (rs10865710), the T --> C (Cys1367Arg) polymorphism of WRN (rs1346044), the -850C --> T polymorphism of TNF (rs1799724), the -219G --> T polymorphism of APOE (rs405509), the C --> T polymorphism of PTGS1 (rs883484) and the 41A --> G (Glu14Gly) polymorphism of ACAT2 (rs9658625) were significantly (P<0.05) associated with the prevalence of CKD. Our results suggest that APOB, WRN, ACAT2, APOE, PPARG, TNF and PTGS1 are susceptibility loci for CKD among Japanese individuals with hypertension. Determination of the genotypes for these polymorphisms may prove informative for the assessment of genetic risk for CKD among such individuals.
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Affiliation(s)
- Tetsuro Yoshida
- Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan
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Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N, Zeitlmann L, Grosse J, Ruf N, Nürnberg P, Costello CM, Onnie C, Mathew C, Platzer M, Schreiber S, Hampe J. Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun 2009; 7:11-8. [PMID: 16222343 DOI: 10.1038/sj.gene.6364263] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Linkage analyses have implicated chromosome 7p21.3 as a susceptibility region for inflammatory bowel disease (IBD). Recently, the mouse phenotype with diarrhea and goblet cell dysfunction caused by anterior gradient protein 2 dysfunction was reported (European patent WO2004056858). The genes encoding for the human homologues AGR2 and AGR3 are localized on chromosome 7p21.3. The gene structures were verified and mutation detection was performed in 47 IBD patients. A total of 30 single nucleotide polymorphisms (SNPs) were tested for association to ulcerative colitis (UC, N = 317) and Crohn's disease (CD, N = 631) in a German cohort and verified in a UK cohort of 384 CD and 311 UC patients. An association signal was identified in the 5' region of the AGR2 gene (most significant SNP hcv1702494, nominal P(TDT) = 0.011, P(case/control) = 0.0007, OR = 1.34, combined cohort). The risk haplotype carried an odds ratio of 1.43 in the German population (P = 0.002). AGR2 was downregulated in UC patients as compared to normal controls (P < 0.001) and a trend toward lower expression was seen in carriers of the risk alleles. Luciferase assays of the AGR2 promoter showed regulation by the goblet cell-specific transcription factors FOXA1 and FOXA2. In summary, AGR2 represents an interesting new avenue into the etiopathophysiology of IBD and the maintenance of epithelial integrity.
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Affiliation(s)
- W Zheng
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
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Polymorphism in ICAM-1, PECAM-1, E-selectin, and L-selectin genes in Tunisian patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2009; 21:167-75. [PMID: 19212205 DOI: 10.1097/meg.0b013e32830e6fc8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) and Crohn's disease (CD) are chronic intestinal disorders characterized by immune dysregulation and leukocytes recruitment into gastrointestinal tract. Cell adhesion molecules (CAM) mediate the extravasation of leukocytes and their accumulation in inflamed intestinal mucosa. Recently, CAM genes have been implicated in determining susceptibility to UC and CD. We investigate seven mutations in CAM: G241R and K469E in ICAM-1, V125L in PECAM-1, G98T, S128R, and L554F in E-selectin and F206L in L-selectin in 197 Tunisian patients (73 with UC and 124 with CD) and 194 controls. These polymorphisms were detected by polymerase chain reaction sequence-specific primers and restriction enzyme analysis. RESULTS A significant increase in allele frequencies of 206L of L-selectin and the associated genotype F/L was observed in both patients with UC and CD compared with controls. Subgroup analysis showed that the L206 allele and F/L206 genotype frequencies were significantly increased in UC patients with left-sided type; whereas, the F/L206 genotype was significant in CD patients with ileocolonic location and stricturing behavior compared with controls. No significant differences in allele or genotype frequencies were observed for ICAM-1 K469E, E-selectin, and PECAM-1 polymorphisms between UC patients, CD patients, and controls. CONCLUSION We found an association of inflammatory bowel disease with allele L206 of L-selectin gene, whereas genotype L/F was associated with a subgroup of UC (left-sided type) and CD patients with more extensive location of disease and stricturing behavior. However, further studies are needed to confirm our findings.
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Cassinotti A, Birindelli S, Clerici M, Trabattoni D, Lazzaroni M, Ardizzone S, Colombo R, Rossi E, Porro GB. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009; 104:195-217; quiz 194, 218. [PMID: 19098870 DOI: 10.1038/ajg.2008.10] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The human leukocyte antigen (HLA) system includes genes involved in graft-vs-host rejection and in immune response. The discovery that HLAs are associated with several diseases led to appealing developments both in basic biomedical research and in clinical medicine, and offered the opportunity to improve the understanding of pathogenesis and classification of diseases, as well as to provide diagnostic and prognostic indicators. The aim of this article is to review the association between HLA alleles and autoimmune digestive disease and its current relationship with modern HLA nomenclature and clinical practice. METHODS Articles dealing with the association between HLAs and autoimmune digestive disease (including celiac disease, inflammatory bowel disease, autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis) were searched for using Pubmed and SCOPUS databases from earliest records to January 2008. RESULTS The review has provided two sections. In the first, we explain the basic principles of HLA structure, function, and nomenclature, as an introduction to the second section, which describes current associations between HLA alleles and digestive diseases. The clinical implications of each HLA association are critically discussed. Actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease. CONCLUSIONS The knowledge of current HLA nomenclature and of its association with some digestive diseases such as celiac disease can be useful in clinical practice for diagnostic and prognostic purposes. This can avoid improper HLA typing as well as stressing the need for further studies on other possible clinical applications.
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Affiliation(s)
- Andrea Cassinotti
- Department of Clinical Science, Division of Gastroenterology, L. Sacco University Hospital, via G.B.Grassi 74, Milan, Italy.
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Hancock L, Beckly J, Geremia A, Cooney R, Cummings F, Pathan S, Guo C, Warren BF, Mortensen N, Ahmad T, Jewell D. Clinical and molecular characteristics of isolated colonic Crohn's disease. Inflamm Bowel Dis 2008; 14:1667-77. [PMID: 18521924 DOI: 10.1002/ibd.20517] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Clinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural history of isolated CD of the colon (Montreal Classification L2) because most studies have not accurately distinguished it from ileocolonic disease. Our objectives were to describe the clinical features and natural history of isolated colonic CD in a rigorously characterized patient cohort and to investigate the association of polymorphisms in a number of genes with colonic location of disease and disease behavior. METHODS Patients with L2 disease were identified from a database of 675 CD patients. Only patients with a normal small bowel enema (70%), ileoscopy alone (30%), or both (20%) were included. Genotyping was performed using PCR-SSP or the iPLEX platform. RESULTS In all, 135 patients were classified with L2 disease. L2 disease was more common in women (74.0% versus 58.0%; P = 0.0004; odds ratio [OR] = 2.11, 95% confidence interval [CI] 1.36-3.26) and in never smokers (48.9% versus 36.9%; P = 0.008; OR = 1.64, 95% CI 1.09-2.45); 20.7% underwent colonic resection for severe disease. We confirmed that carriage of the HLA-DRB1*0103 allele is strongly associated with isolated colonic CD (14.9% versus 4.0%; P = 0.000016; OR 4.6, 95% CI 2.25-9.47) and report the novel association of this allele with time to first surgical event (log rank P = 0.001). There was no association with any of the known CD susceptibility loci (NOD2, IBD5, NOD1, IL23R, ATG16L1) and isolated colonic CD. A nonsynonymous polymorphism in MEKK1 (rs832582) was associated with CD susceptibility overall (15% versus 19%; P = 0.0083; OR = 1.28, 95% CI 1.07-1.54). The association was strongest in those patients not carrying a NOD2 mutation and had no effect on disease location. CONCLUSIONS This study describes the clinical features of isolated colonic CD and demonstrates the importance of the HLA region in determining the molecular basis of colonic inflammation.
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Affiliation(s)
- Laura Hancock
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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Yan Y, Merlin D. Ste20-related proline/alanine-rich kinase: A novel regulator of intestinal inflammation. World J Gastroenterol 2008; 14:6115-21. [PMID: 18985800 PMCID: PMC2761571 DOI: 10.3748/wjg.14.6115] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [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
Recently, inflammatory bowel disease (IBD) has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase (SPAK) is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases (such as p38, JNK, NKCC1, PKCtheta;, WNK and MLCK), and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport. This review examines the involvement of Ste20-like kinases and downstream mitogen-activated protein kinases (MAPKs) pathways in the pathogenesis and control of intestinal inflammation. The primary focus will be on the molecular features of intestinal inflammation, with an emphasis on the interaction between SPAK and other molecules, and the effect of these interactions on homeostatic maintenance, cell volume regulation and increased cell permeability in intestinal inflammation.
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Matsumura Y, Kinouchi Y, Nomura E, Negoro K, Kakuta Y, Endo K, Aizawa H, Takagi S, Takahashi S, Shimosegawa T. HLA-DRB1 alleles influence clinical phenotypes in Japanese patients with ulcerative colitis. ACTA ACUST UNITED AC 2008; 71:447-52. [PMID: 18416774 DOI: 10.1111/j.1399-0039.2008.01031.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR)=2.20, Pc=0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR=2.31, Pc=0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese.
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Affiliation(s)
- Y Matsumura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Lappalainen M, Halme L, Turunen U, Saavalainen P, Einarsdottir E, Färkkilä M, Kontula K, Paavola-Sakki P, Lanchbury JS, Merriman TR, Barclay ML, Kennedy MA. Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population. Inflamm Bowel Dis 2008; 14:1118-24. [PMID: 18338763 DOI: 10.1002/ibd.20431] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATG16L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients. METHODS A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method. RESULTS Five markers spanning the IL23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants. CONCLUSIONS We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.
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Crusius JBA, Canzian F, Capellá G, Peña AS, Pera G, Sala N, Agudo A, Rico F, Del Giudice G, Palli D, Plebani M, Boeing H, Bueno-de-Mesquita HB, Carneiro F, Pala V, Save VE, Vineis P, Tumino R, Panico S, Berglund G, Manjer J, Stenling R, Hallmans G, Martínez C, Dorronsoro M, Barricarte A, Navarro C, Quirós JR, Allen N, Key TJ, Binghan S, Caldas C, Linseisen J, Kaaks R, Overvad K, Tjønneland A, Büchner FC, Peeters PHM, Numans ME, Clavel-Chapelon F, Trichopoulou A, Lund E, Jenab M, Rinaldi S, Ferrari P, Riboli E, González CA. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST). Ann Oncol 2008; 19:1894-902. [PMID: 18628242 DOI: 10.1093/annonc/mdn400] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The relative contribution to gastric cancer (GC) risk of variants in genes that determine the inflammatory response remains mostly unknown and results from genotyping studies are inconsistent. PATIENTS AND METHODS A nested case-control study within the prospective European Prospective Investigation into Cancer and Nutrition cohort was carried out, including 248 gastric adenocarcinomas and 770 matched controls. Twenty common polymorphisms at cytokine genes [interleukin (IL)1A, IL1B, IL1RN, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, lymphotoxin alpha and tumor necrosis factor (TNF)] were analyzed. Antibodies against Helicobacter pylori (Hp) and CagA were measured. RESULTS IL1RN 2R/2R genotype [odds ratio (OR) 2.43; 95% confidence interval (CI) 1.19-4.96] and allele IL1RN Ex5-35C were associated with an increased risk of Hp(+) non-cardia GC. IL8 -251AA genotype was associated with a decreased risk of Hp(+) non-cardia GC (OR 0.51; 95% CI 0.32-0.81), mainly of the intestinal type. These associations were not modified by CagA status. Carriers of IL1B -580C and TNF -487A alleles did not associate with an increased risk. A moderately increased risk of Hp(+) non-cardia GC for IL4R -29429T variant was observed (OR 1.74; 95% CI 1.15-2.63). CONCLUSION This prospective study confirms the association of IL1RN polymorphisms with the risk of non-cardia GC and indicates that IL8 -251T>A may modify the risk for GC.
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Affiliation(s)
- J B A Crusius
- Laboratory of Immunogenetics, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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Shugart YY, Silverberg MS, Duerr RH, Taylor KD, Wang MH, Zarfas K, Schumm LP, Bromfield G, Steinhart AH, Griffiths AM, Kane SV, Barmada MM, Rotter JI, Mei L, Bernstein CN, Bayless TM, Langelier D, Cohen A, Bitton A, Rioux JD, Cho JH, Brant SR. An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29. Genes Immun 2008; 9:161-7. [PMID: 18246054 PMCID: PMC3858857 DOI: 10.1038/sj.gene.6364460] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Accepted: 12/14/2007] [Indexed: 11/08/2022]
Abstract
Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.
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Affiliation(s)
- YY Shugart
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - MS Silverberg
- Department of Medicine, Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - RH Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - KD Taylor
- Division of Medical Genetics and Inflammatory Bowel Disease Center, Cedar-Sinai Medical Center, Los Angeles, CA, USA
| | - M-H Wang
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - K Zarfas
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - LP Schumm
- Department of Medicine and Department of Health Science, The University of Chicago, Chicago, IL, USA
| | - G Bromfield
- Department of Medicine and Department of Health Science, The University of Chicago, Chicago, IL, USA
| | - AH Steinhart
- Department of Medicine, Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - AM Griffiths
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - SV Kane
- Department of Medicine and Department of Health Science, The University of Chicago, Chicago, IL, USA
| | - MM Barmada
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - JI Rotter
- Division of Medical Genetics and Inflammatory Bowel Disease Center, Cedar-Sinai Medical Center, Los Angeles, CA, USA
| | - L Mei
- Division of Medical Genetics and Inflammatory Bowel Disease Center, Cedar-Sinai Medical Center, Los Angeles, CA, USA
| | - CN Bernstein
- Section of Gastroenterology, University of Manitoba John Buhler Research Centre, Winnipeg, Manitoba, Canada
| | - TM Bayless
- Department of Medicine, Harvey M and Lyn P Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D Langelier
- Service de gastro-entérologie, Centre hospitalier universitaire de Sherbrooke Hôpital, Fleurimont, Quebec, Canada
| | - A Cohen
- Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - A Bitton
- Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada
| | - JD Rioux
- Department of Medicine, Université de Montréal, Montréal Heart Institute, Montreal, Quebec, Canada
| | - JH Cho
- Department of Medicine and Genetics, Yale University School of Medicine, New Haven, CT, USA
| | - SR Brant
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
- Department of Medicine, Harvey M and Lyn P Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Roberts RL, Gearry RB, Hollis-Moffatt JE, Miller AL, Reid J, Abkevich V, Timms KM, Gutin A, Lanchbury JS, Merriman TR, Barclay ML, Kennedy MA. IL23R R381Q and ATG16L1 T300A are strongly associated with Crohn's disease in a study of New Zealand Caucasians with inflammatory bowel disease. Am J Gastroenterol 2007; 102:2754-61. [PMID: 17894849 DOI: 10.1111/j.1572-0241.2007.01525.x] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Recently, separate genome-wide association analyses have identified nonsynonymous SNPs in IL23R and ATG16L1 (rs11209026; c1142G>A, R381Q, and rs2241880; c1338A>G, T300A, respectively) as strong candidate susceptibility factors for Crohn's disease (CD) in whites. The aim of our study was to test whether these SNPs are associated with CD in a population-based cohort of New Zealand Caucasian inflammatory bowel disease (IBD) patients. METHODS Allele frequencies of rs11209026 and rs2241880 were determined in 496 CD patients, 466 ulcerative colitis (UC) patients, and 591 controls. Distribution of the relevant alleles was compared between controls and IBD patients. rs11209026 and rs2241880 genotype distributions were examined both within IBD clinical subphenotypes and CARD15 genotypes. RESULTS rs11209026 and rs2241880 were both associated with CD (P valuers11209026=0.0026, OR 0.54, 95% CI 0.36-0.81; P valuers2241880=0.0001, OR 1.41, 95% CI 1.18-1.67). In addition, there was evidence for association of rs11209026 with UC (P value=0.037, OR 0.66, 95% CI 0.45-0.98). No significant association was observed between IL23R genotype or ATG16L1 genotype and IBD subphenotypes. IL23R was associated with CD and UC only in the absence of CARD15 mutations, whereas ATG16L1 was associated with CD in the presence and absence of CARD15 mutations. CONCLUSIONS We replicated the previously reported associations between CD and rs11209026 and rs2241880, confirming that IL23R and ATG16L1 are susceptibility loci for CD in the New Zealand population. We also provide further evidence for association of rs11209026 with UC and a report of an additive effect between IL23R and CARD15 genotypes in CD.
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Affiliation(s)
- Rebecca L Roberts
- Department of Pathology, University of Otago, Christchurch School of Medicine & Health Sciences, Christchurch, New Zealand
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Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a clinically and, likely, genetically heterogeneous group of disorders. A recent report suggests that genetic variations in the TNFSF15 gene contribute to the susceptibility of IBD in both Japanese and Caucasian populations. The aim was to confirm the association between TNFSF15 high- and low-risk haplotypes and IBD in a Caucasian population. METHODS Five single-nucleotide polymorphisms (SNPs) that comprise the 2 common haplotypes were genotyped in 599 Caucasian patients with Crohn's disease (CD), 382 Caucasian patients with ulcerative colitis (UC), and 230 ethnically matched healthy controls, including both Jews and non-Jews. RESULTS The previously reported 'risk' haplotype was not associated with CD or UC (88.2% in CD cases versus 88.3% in controls, P = 0.96; 88.1% in UC cases versus 88.3% in controls, P = 0.78). We did, however, observe an increased frequency of the "protective" haplotype in non-Jewish controls for both CD and UC (38.8% CD cases versus 50% controls, P = 0.01; 37.3% UC cases versus 50% controls, P = 0.01) with no such effect observed in the Jewish samples. There was an interactive effect between ethnicity and the protective haplotype in CD (P = 0.04). CONCLUSIONS We observed a protective haplotype, consisting of the minor alleles for all 5 markers, to have a higher frequency in the non-Jewish controls than in CD and UC. Of further interest, the haplotype frequency was in the opposite direction in our Jewish case-control panels (both CD and UC), leading us to conclude 1) that TNFSF15 is indeed an IBD susceptibility gene, and 2) the disease susceptibility is ethnic-specific.
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Affiliation(s)
- Yoana Picornell
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Ling Mei
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Kent Taylor
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Huiying Yang
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Stephan R. Targan
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA 90048
| | - Jerome I. Rotter
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
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Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, Bayless TM, Parmigiani G, Chakravarti S. Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Dis 2007; 13:807-21. [PMID: 17262812 DOI: 10.1002/ibd.20110] [Citation(s) in RCA: 217] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBD) with variable, overlapping clinical features and complex pathophysiologies. METHODS To identify pathogenic processes underlying these disease subtypes, we used single endoscopic pinch biopsies to elucidate patterns of gene expression in active and inactive areas of UC and CD and compared these to infectious colitis and healthy control samples. RESULTS Unsupervised classification of a total of 36 samples yielded promising separation between the affected IBD, unaffected IBD, non-IBD colitis, and normal control samples, suggesting each sample type had a distinctive gene expression pattern. Genes differentially expressed in the CD samples compared to in the controls were related to IFNgamma-inducible TH1 processes (IFITM1, IFITM3, STAT1, and STAT3) and antigen presentation (TAP1, PSME2, PSMB8). The most noticeable change in the UC samples was reduced expression of genes regulating biosynthesis, metabolism, and electrolyte transport (HNF4G, KLF5, AQP8, ATP2B1, and SLC16A). Twenty-five percent of genes down-regulated in the UC samples were also down-regulated in the infectious colitis samples. Unaffected biopsy samples of IBD patients also registered differences expression of genes compared to in the normal controls. Of these differentially expressed genes, only 2 were up-regulated, PSKH1, a regulator of mRNA processing, and PPID, a suppressor of apoptosis. CONCLUSIONS The study shows that the gene expression patterns of IBD, CD in particular, are quite different from those of infectious colitis, highlighting distinctive expression of genes and pathways in UC and CD.
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Affiliation(s)
- Feng Wu
- Department of Medicine (Gastroenterology Division), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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Abstract
Standard of care for ulcerative colitis involves long-term pharmacotherapy or colectomy. Approximately 20% to 30% of patients eventually require a colectomy because patients either do not respond or cannot tolerate the currently available pharmacotherapies. Advances in our knowledge of the pathophysiology of ulcerative colitis have highlighted the importance of cytokines such as tumor necrosis factor alpha (TNFalpha) in the inflammatory process. TNFalpha is a proinflammatory mediator that plays an integral role in the pathogenesis of inflammatory bowel disease. In addition, mounting evidence indicates a genetic association between TNFalpha and ulcerative colitis. Furthermore, increased TNFalpha levels have been demonstrated in studies of patients with ulcerative colitis. TNFalpha is likely an important component in the pathophysiology of ulcerative colitis, and thus agents targeting TNFalpha in ulcerative colitis have been studied. Recent randomized controlled trials have confirmed that biologic anti-TNFalpha therapy is effective in ulcerative colitis. Soluble TNFalpha receptors or biologic agents that suppress or inhibit TNFalpha production may also show therapeutic promise.
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Affiliation(s)
- Bruce E Sands
- Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Diseases, and MGH Crohn's and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
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