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Marabi MH, Mozaffari HR, Ghasemi H, Hatami M, Yari K. Evaluation of the association between TNF-α-1031 T/C polymorphism with oral lichen planus disease. BMC Oral Health 2024; 24:189. [PMID: 38317095 PMCID: PMC10845614 DOI: 10.1186/s12903-024-03939-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 01/25/2024] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Oral lichen planus (OLP) is a T-cell-mediated autoimmune disease that affects the epithelial cells of the oral cavity. This study was performed to investigate any possible relationship between - 1031(T/C) polymorphism (rs1799964) of the tumor necrosis factor α (TNF-α) gene with the risk and severity of oral lichen planus (OLP) disease among an Iranian population. METHOD Saliva samples were collected from 100 patients with OLP and a similar number of healthy controls (age and sex-matched). Then, DNA was extracted from the collected samples for genotyping TNF-α-1031 T/C polymorphism using the PCR-CTPP method. The results were assessed using SPSS software. RESULTS The findings revealed a significantly higher prevalence of the C allele in OLP patients (53%) compared to healthy controls (36%), suggesting an association between TNF-alpha gene polymorphism and OLP. A multivariate logistic regression analysis supported this finding, as the presence of the C allele was significantly associated with an increased risk of OLP [χ2 = 4.17, p = 0.04, 95% CI = 1.01-2.65, OR = 1.64]. However, our data indicated no significant association between TNF-alpha-1031 T/C gene polymorphism and OLP severity. CONCLUSIONS These findings provide the first evidence supporting a possible role of TNF-α-1031 T/C gene polymorphism in OLP susceptibility in the Iranian population. The findings of this study demonstrate a positive association between TNF-α-1031 C/T allele distribution and the risk of OLP disease in the Iranian population. Therefore, carrying the C allele may increase the susceptibility to OLP disease.
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Affiliation(s)
- Mohammad Hesam Marabi
- Student Research Committee, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamid Reza Mozaffari
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Haniyeh Ghasemi
- Student Research Committee, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Hatami
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kheirollah Yari
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Fu L, Lei C, Chen Y, Zhu R, Zhuang M, Dong L, Ye X, Zheng L, Gong D. TNF-α-1031T/C gene polymorphism as a predictor of malnutrition in patients with gastric cancer. Front Nutr 2023; 10:1208375. [PMID: 37533569 PMCID: PMC10393265 DOI: 10.3389/fnut.2023.1208375] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
Introduction Malnutrition is a complex clinical syndrome, the exact mechanism of which is yet not fully understood. Studies have found that malnutrition is associated with anorexia and inadequate intake, tumor depletion, leptin, tumor-induced metabolic abnormalities in the body, and catabolic factors produced by the tumor in the circulation and cytokines produced by the host immune system. Among these, single nucleotide polymorphisms (SNPs) are present in the gene encoding the pro-inflammatory cytokine TNF-α. Aim The objective of this study was to investigate TNF-α -1,031 T/C gene polymorphism as an unfavorable predictor of malnutrition in patients with gastric cancer. Methods The study group consisted of 220 gastric cancer patients treated at Affiliated Jinhua Hospital, Zhejiang University School of Medicine. Malnutrition was mainly assessed by the Global Consensus on Malnutrition Diagnostic Criteria (GLIM). DNA was extracted from peripheral leukocytes of whole blood samples using an animal DNA extraction kit. DNA was amplified using a 1.1× T3 Super PCR mixture and genotyped using SNP1 software. Results There are three major genetic polymorphisms in TNF-α. Among the 220 patients with gastric cancer, there were 7 patients with the CC genotype, 61 with the CT genotype and 152 with the TT genotype. Compared to patients with the TT genotype, patients with the C allele had an approximately 2.5-fold higher risk of developing malnutrition (p = 0.003; OR = 0.406). On the basis of multivariate analysis, patients with the CC genotype had an approximately 20.1-fold higher risk of developing malnutrition (p = 0.013; OR = 20.114), while those with the CT genotype had an almost 3.7-fold higher risk of malnutrition (p = 0.002; OR = 3.218). Conclusion SNP (-1,031 T/C) of the TNF-α may be a useful marker in the assessment of the risk of nutritional deficiencies in gastric cancer patients. Patients with gastric cancer carrying the C allele should be supported by early nutritional intervention, but more research is still needed to explore confirmation.
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Affiliation(s)
- Liang Fu
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Changzhen Lei
- Department of Gastrointestinal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yingxun Chen
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ruiyun Zhu
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Minling Zhuang
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Liping Dong
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Xianghong Ye
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Lushan Zheng
- Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Daojun Gong
- Department of Gastrointestinal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
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Sun A, Li W, Shang S. Association of polymorphisms in the
IL‐10
promoter region with Crohn's disease. J Clin Lab Anal 2022; 36:e24780. [DOI: 10.1002/jcla.24780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 11/22/2022] Open
Affiliation(s)
- Anna Sun
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center For Child Health Hangzhou China
| | - Wei Li
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center For Child Health Hangzhou China
| | - Shiqiang Shang
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center For Child Health Hangzhou China
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Krovi SH, Kuchroo VK. Activation pathways that drive CD4 + T cells to break tolerance in autoimmune diseases . Immunol Rev 2022;307:161-190. [PMID: 35142369 PMCID: PMC9255211 DOI: 10.1111/imr.13071] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 12/11/2022]
Abstract
Autoimmune diseases are characterized by dysfunctional immune systems that misrecognize self as non-self and cause tissue destruction. Several cell types have been implicated in triggering and sustaining disease. Due to a strong association of major histocompatibility complex II (MHC-II) proteins with various autoimmune diseases, CD4+ T lymphocytes have been thoroughly investigated for their roles in dictating disease course. CD4+ T cell activation is a coordinated process that requires three distinct signals: Signal 1, which is mediated by antigen recognition on MHC-II molecules; Signal 2, which boosts signal 1 in a costimulatory manner; and Signal 3, which helps to differentiate the activated cells into functionally relevant subsets. These signals are disrupted during autoimmunity and prompt CD4+ T cells to break tolerance. Herein, we review our current understanding of how each of the three signals plays a role in three different autoimmune diseases and highlight the genetic polymorphisms that predispose individuals to autoimmunity. We also discuss the drawbacks of existing therapies and how they can be addressed to achieve lasting tolerance in patients.
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Affiliation(s)
- Sai Harsha Krovi
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Chlorogenic acid supplementation alleviates dextran sulfate sodium (DSS)-induced colitis via inhibiting inflammatory responses and oxidative stress, improving gut barrier integrity and Nrf-2/HO-1 pathway. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104808] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
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Liu M, Yuan W, Park S. Association between IL-10 rs3024505 and susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Cytokine 2021; 149:155721. [PMID: 34628128 DOI: 10.1016/j.cyto.2021.155721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/03/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the small intestine, colon, and rectum. We evaluated associations between the interleukin 10 (IL-10) rs3024505 polymorphism and IBD, ulcerative colitis (UC), and Crohn's disease (CD) by meta-analysis. All peer-reviewed manuscripts concerning the relationship between IL-10_rs3024505 and IBD identified by searing the PubMed, Cochrane Library, EMBASE, and Chinese Medical Database were examined. The association between IL-10_rs3024505 and IBD was evaluated in allele (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Associations were also conducted on IBD subtypes, CD and UC, and ethnicity (Non-Europeans and Europeans) subgroups. The meta-analysis included 13 studies, 8552 cases (IBD patients), and 12,830 healthy controls. Subgroup analysis of IBD (UC and CD) revealed heterogeneity in AG, DG, and HTG but no heterogeneity in RG or HMG. Moreover, AG, DG, and HTG did not show publication bias in IBD, CD, or UC, but RG and HMG exhibited publication bias. No heterogeneity and no publication bias were found among the five genetic models by a subgroup analysis of Non-Europeans and European ethnicities. The minor allele(T) of rs3024505 was significantly related to IBD: 1.37 (1.30-1.45) for AG, 2.06 (1.74-2.45) for RG, 1.39 (1.27-1.52) for DG, 2.25 (1.89-2.67) for HMG, and 1.32 (1.23-1.40) for HTG (all P < 0.00001). In the subgroup analysis of ethnicity, there was a significant effect of rs3024505 on IBD in Europeans but not non-Europeans: 1.38 (1.31-1.46) for AG, 2.07 (1.73-2.48) for RG, 1.39 (1.31-1.49) for DG, 2.26 (1.89-2.71) for HMG, and 1.33 (1.24-1.42) for HTG in Europeans (all P < 0.00001). Sensitivity analysis showed no dominant study in Europeans, but one study had a dominant impact in Non-Europeans. In conclusion, IL-10_rs3024505 polymorphism confers susceptibility to CD and UC in Europeans, but its impact should have conducted more studies in Non-Europeans.
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Affiliation(s)
- Meiling Liu
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Chungnam 31499, Republic of Korea
| | - Wang Yuan
- Dept. of Bio-Convergence System, Hoseo University, Asan, 31499, Republic of Korea
| | - Sunmin Park
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Chungnam 31499, Republic of Korea; Dept. of Bio-Convergence System, Hoseo University, Asan, 31499, Republic of Korea.
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Abstract
Interleukin (IL)-10 is an essential anti-inflammatory cytokine and functions as a negative regulator of immune responses to microbial antigens. IL-10 is particularly important in maintaining the intestinal microbe-immune homeostasis. Loss of IL-10 promotes the development of inflammatory bowel disease (IBD) as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions more generally to prevent excessive inflammation during the course of infection. Although IL-10 can be produced by virtually all cells of the innate and adaptive immune system, T cells constitute a non-redundant source for IL-10 in many cases. The various roles of T cell-derived IL-10 will be discussed in this review. Given that IL-10 is at the center of maintaining the delicate balance between effective immunity and tissue protection, it is not surprising that IL-10 expression is highly dynamic and tightly regulated. We summarize the environmental signals and molecular pathways that regulate IL-10 expression. While numerous studies have provided us with a deep understanding of IL-10 biology, the majority of findings have been made in murine models, prompting us to highlight gaps in our knowledge about T cell-derived IL-10 in the human system.
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Ebrahimi Daryani N, Saghazadeh A, Moossavi S, Sadr M, Shahkarami S, Soltani S, Farhadi E, Rezaei N. Interleukin-4 and Interleukin-10 Gene Polymorphisms in Patients with Inflammatory Bowel Disease. Immunol Invest 2018; 46:714-729. [PMID: 28872970 DOI: 10.1080/08820139.2017.1360343] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Changes in cytokine expression have been frequently found in patients with inflammatory bowel disease (IBD). Cytokine values outside the normal range may be somewhat related to common polymorphisms within cytokine genes. OBJECTIVE The present study was designed to investigate the possible association between polymorphisms within Interleukin IL-4 and IL-10 genes and susceptibility to and clinical features of IBD. METHODS The study population was composed of 140 healthy controls and 75 patients with IBD (40 patients with Crohn's disease (CD) and 35 patients with ulcerative colitis (UC)). Genotyping was performed using polymerase chain reaction with sequence-specific primers. RESULTS Higher frequencies for the C allele of IL-4-590 polymorphism (P < 0.0001; odds ratio [OR], 5.68; 95% confidence interval [95% CI], 3.28-9.83) and for the T allele of IL-4-1098 polymorphism (P = 0.016; OR, 1.83; 95% CI, 1.11-3.02) were observed in the whole group of IBD patients. The IL-4-590 C allele was also significantly overrepresented when IBD patients were subdivided into CD and UC (P < 0.0001; OR, 5.2-6.28). While the IL-4-1098 T allele was present at higher frequencies in patients with UC (P = 0.05; OR, 1.95), but not in CD (P = 0.09). Multiple pairwise comparisons indicated that genotypes of all polymorphisms investigated within IL-4 gene are correlated with IBD, CD, and UC. Haplotype analysis showed that the IL-4-1098/-590 TC haplotype might predispose individuals to IBD, CD, and UC whereas the IL-4-1098/-590 TT and GC haplotypes have a protective effect. On the contrary, neither allele nor genotype frequencies of IL-10 polymorphisms (IL-10-1082 A > G, IL-10-592 A > C, and IL-10-819 T > C) were associated with IBD, CD, or UC. CONCLUSIONS The present study suggests that IL-4 polymorphisms might play a role in susceptibility to IBD and its major subtypes in the Iranian population.
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Affiliation(s)
- Nasser Ebrahimi Daryani
- a Department of Gastroenterology and Hepatology , Tehran University of Medical Sciences , Tehran , Iran
| | - Amene Saghazadeh
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran.,c Systematic Review and Mata-analysis Expert Group (SRMEG) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Shirin Moossavi
- d Digestive Oncology Research Center, Digestive Disease Research Institute , Tehran University of Medical Sciences , Tehran , Iran
| | - Maryam Sadr
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Sepideh Shahkarami
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran.,e Medical Genetics Network (MeGeNe) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Samaneh Soltani
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Elham Farhadi
- f Hematology Department , School of Allied Medical Science, Iran University of Medical Sciences , Tehran , Iran
| | - Nima Rezaei
- g Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,h Department of Immunology , School of Medicine, Tehran University of Medical Sciences , Tehran , Iran.,i Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
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9
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Imam T, Park S, Kaplan MH, Olson MR. Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 2018; 9:1212. [PMID: 29910812 PMCID: PMC5992276 DOI: 10.3389/fimmu.2018.01212] [Citation(s) in RCA: 194] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/15/2018] [Indexed: 12/30/2022] Open
Abstract
The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.
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Affiliation(s)
- Tanbeena Imam
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sungtae Park
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Mark H Kaplan
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Matthew R Olson
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
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10
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Powrózek T, Mlak R, Brzozowska A, Mazurek M, Gołębiowski P, Małecka-Massalska T. Relationship between TNF-α -1031T/C gene polymorphism, plasma level of TNF-α, and risk of cachexia in head and neck cancer patients. J Cancer Res Clin Oncol 2018; 144:1423-1434. [PMID: 29802455 PMCID: PMC6061036 DOI: 10.1007/s00432-018-2679-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/22/2018] [Indexed: 12/22/2022]
Abstract
Background Malnutrition and cachexia are frequent among head and neck cancer (HNC) patients and these syndromes are associated with both poor quality of life and unfavorable disease prognosis. Unfortunately, there are still no established biomarkers that could predict the development of cachexia. Among potential molecular alterations related to cancer cachexia, there are single-nucleotide polymorphisms (SNPs) within genes encoding pro-inflammatory cytokines such as TNF-α. The aim of the study To investigate TNF-α −1031T/C SNP as a risk factor of cachexia in 62 HNC patients subjected to radiotherapy. DNA was isolated from whole blood samples and genotyping was conducted using real-time PCR method by means of TaqMan SNP Genotyping Assay. TNF-alpha Human ELISA Kit was used to determine TNF-α concentration in each extracted plasma sample. Moreover, the relationship between genotype variants of TNF-α and plasma level of TNF-α was examined. Detailed clinical–demographic and nutritional data were collected from each study participant. Results CC genotype carriers were at a significantly higher risk of being qualified as cachectic compared with other genotype carriers (p = 0.044; HR = 3.724). Subjects, who carried CC genotype had significantly lower body mass compared to patients with TT and CT genotype (p = 0.045). Moreover, CC individuals had the highest TNF-α plasma level (median 10.70 ± 0.72 pg/mL, p = 0.006) among the studied cases. We also noted, that CC genotype carriers had significantly higher risk of early death incidence compared to other genotype carriers [overall survival (OS): 28 vs 38 months (HR = 3.630, p = 0.013)]. Conclusion Despite the differences between SGA and NRS scoring, the presence of CC genotype could be a useful objective marker allowing for the prediction of cachexia development in both parenterally nourished and non-parenterally nourished patients. Patients with CC genotype had also the highest risk of early death incidence; therefore, such individuals should be qualified for parenteral nutrition and supportive care at the time of diagnosis to improve further therapy outcomes. Moreover, this is the first study demonstrating the relationship between TNF-α −1031T/C polymorphism and plasma level of TNF-α. This is also the first paper investigating the role of TNF-α −1031T/C in cancer cachexia.
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Affiliation(s)
- Tomasz Powrózek
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland.
| | - Radosław Mlak
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Anna Brzozowska
- Department of Oncology, Medical University of Lublin, Lublin, Poland
| | - Marcin Mazurek
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Paweł Gołębiowski
- Department of Oncology, Medical University of Lublin, Lublin, Poland
| | - Teresa Małecka-Massalska
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
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Nourian M, Chaleshi V, Pishkar L, Azimzadeh P, Baradaran Ghavami S, Balaii H, Alinaghi S, Shahrokh S, Asadzadeh Aghdaei H, Zali MR. Evaluation of tumor necrosis factor (TNF)-α mRNA expression level and the rs1799964 polymorphism of the TNF-α gene in peripheral mononuclear cells of patients with inflammatory bowel diseases. Biomed Rep 2017; 6:698-702. [PMID: 28584644 PMCID: PMC5449959 DOI: 10.3892/br.2017.908] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Accepted: 04/04/2017] [Indexed: 12/16/2022] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are types of chronic inflammatory bowel disease (IBD) of which the actual causes remain unknown. Emerging data indicate that alterations in cytokine synthesis may be involved in IBD pathogenesis. The aim of the present study was to determine whether the tumor necrosis factor (TNF)-α mRNA expression level and rs1799964 polymorphism are the genetic susceptibility component of IBD development. The TNF-α mRNA expression level of peripheral blood mononuclear cells (PBMCs) was measured using comparative reverse-transcription quantitative polymerase chain reaction (PCR). Genomic DNA from 201 individuals (CD: n=15; UC: n=86; control subjects: n=100) was analyzed for the presence of the TNF-α-1031 polymorphism by PCR-restriction fragment length polymorphism. An increased TNF-α mRNA expression level was additionally observed in the CC genotype of the -1031 TNF-α gene polymorphism compared with the TC and TT genotypes (P<0.05). Furthermore, the present results revealed that there was no significant difference in the genotype/allele frequencies of the -1031 TNF-α gene polymorphism in Iranian IBD patients. By comparison, the TNF-α mRNA expression level was evaluated in patients with a history of taking medications and demonstrated a significant association in the group that received the 5-ASA + Pred + AZA,5. 5-ASA + Pred + AZA + IFX when compared with the other groups (P<0.05). Thus, these results support the hypothesis that overexpression of the TNF-α gene, which correlated with the CC genotype, may represent a genetic risk factor for Iranian IBD.
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Affiliation(s)
- Mahyar Nourian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Vahid Chaleshi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Leila Pishkar
- Young Researchers and Elite Club, Islamshahr Branch, Islamic Azad University, Islamshahr 3314767653, Iran
| | - Pedram Azimzadeh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Hedieh Balaii
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Samaneh Alinaghi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Hamid Asadzadeh Aghdaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
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Mijac D, Petrovic IV, Djuranovic S, Perovic V, Bojic D, Culafic D, Popovic D, Krstic M, Jankovic G, Djoric M, Pravica V, Markovic M. The Polymorphism rs3024505 (C/T) Downstream of the IL10 Gene Is Associated with Crohn's Disease in Serbian Patients with Inflammatory Bowel Disease. TOHOKU J EXP MED 2017; 240:15-24. [PMID: 27558476 DOI: 10.1620/tjem.240.15] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Inflammatory bowel disease (IBD), manifesting as Crohn's disease (CD) and ulcerative colitis (UC), is characterized by recurring episodes of inflammation in gastrointestinal tract, in which aberrant production of regulatory cytokine interleukin-10 (IL-10) presumably plays important role. Single nucleotide polymorphisms (SNPs) that affect IL-10 production, such as rs1800896 (G/A) at position -1082 and rs1800871 (C/T) at position -819 in the promoter region of the IL10 gene, have been associated with CD and/or UC, but the results were inconsistent. Another SNP that may alter IL-10 production, rs3024505 (C/T) located immediately downstream of the IL10 gene has been recently identified. T allele of rs3024505 was associated with both UC and CD in Western populations, but the studies from East European countries are lacking. Therefore, our aim was to assess the association of rs3024505, rs1800896 and rs1800871 with Serbian IBD patients. To this end, 107 CD and 99 UC patients and 255 healthy controls were genotyped. As a result, T allele of rs3024505 was associated with CD at allelic, genotypic (GT genotype) and haplotypic (GCCT haplotype) level, suggesting potential role of this variant in susceptibility to CD. In contrast, CD patients carrying C allele of rs3024505 had significantly increased risk of anemia and stricturing/penetrating behavior. No association was observed between rs3024505 and UC or SNPs in IL10 promoter region and any form of IBD. In conclusion, rs3024505 SNP flanking the IL10 gene is associated with susceptibility and severity of disease in Serbian CD patients, further validating its role as a potential biomarker in IBD.
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Affiliation(s)
- Dragana Mijac
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, School of Medicine, University of Belgrade
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Wu H, Guo J, He Y, Yin H, Shu J. Relationship between IL-10 gene -819C/T polymorphism and the risk of inflammatory bowel disease: a meta-analysis. Afr Health Sci 2016; 16:866-872. [PMID: 27917223 DOI: 10.4314/ahs.v16i3.30] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The -819C/T polymorphism in interleukin 10 (IL-10) gene has been reported to be associated with inflammatory bowel disease (IBD), but the previous results are conflicting. MATERIALS AND METHODS The present study aimed at investigating the association between this polymorphism and risk of IBD using a meta-analysis.PubMed, Web of Science,EMBASE,google scholar and China National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant publications from their inception to April 2016.Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects models. RESULTS A total of 7 case-control studies containing 1890 patients and 2929 controls were enrolled into this meta-analysis, and our results showed no association between IL-10 gene -819C/T polymorphism and IBD risk(TT vs. CC:OR=0.81,95%CI 0.64-1.04;CT vs. CC:OR=0.92,95%CI 0.81-1.05; Dominant model: OR=0.90,95%CI 0.80-1.02; Recessive model: OR=0.84,95%CI 0.66-1.06). In a subgroup analysis by nationality, the -819C/T polymorphism was not associated with IBD in both Asians and Caucasians. In the subgroup analysis stratified by IBD type, significant association was found in Crohn's disease(CD)(CT vs. CC:OR=0.68,95%CI 0.48-0.97). CONCLUSION In summary, the present meta-analysis suggests that the IL-10 gene -819C/T polymorphism may be associated with CD risk.
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Affiliation(s)
- Haien Wu
- Department of Gastroenterology, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China; Department of Gastroenterology, Jiangmen Central Hospital, Jiangmen 529030, China
| | - JingJing Guo
- Department of Nephrology, Jiangmen Central Hospital, Jiangmen 529030, China
| | - Yajun He
- Center of Clinical Laboratory Medicine, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China
| | - Hekun Yin
- Department of Gastroenterology, Jiangmen Central Hospital, Jiangmen 529030, China
| | - Jianchang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China
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Tavares M, de Lima C, Fernandes W, Martinelli V, de Lucena M, Lima F, Telles A, Brandão L, de Melo Júnior M. Tumour necrosis factor-alpha (-308G/A) promoter polymorphism is associated with ulcerative colitis in Brazilian patients. Int J Immunogenet 2016; 43:376-382. [DOI: 10.1111/iji.12289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 06/13/2016] [Accepted: 07/28/2016] [Indexed: 01/26/2023]
Affiliation(s)
- M. Tavares
- Laboratory of Immunopathology Keizo Asami; Federal University of Pernambuco; Recife Brazil
| | - C. de Lima
- Laboratory of Immunopathology Keizo Asami and Department of Genetics; Federal University of Pernambuco; Recife Brazil
| | - W. Fernandes
- Master in Pathology; Federal University of Pernambuco; Recife Brazil
| | - V. Martinelli
- Department of Gastroenterology; University Hospital; Federal University of Pernambuco; Recife Brazil
| | - M. de Lucena
- Maurílio Toscano de Lucena; Department of Proctology; Barão de Lucena Hospital; Recife Brazil
| | - F. Lima
- Department of Surgery; University Hospital; Federal University of Pernambuco; Recife Brazil
| | - A. Telles
- Department of Pathology; Federal University of Pernambuco; Recife Brazil
| | - L. Brandão
- Department of Pathology; Federal University of Pernambuco; Recife Brazil
| | - M. de Melo Júnior
- Department of Pathology; Federal University of Pernambuco; Recife Brazil
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Atoum MF. ACC interleukin-10 gene promoter haplotype as a breast cancer risk factor predictor among Jordanian females. Onco Targets Ther 2016; 9:3353-3357. [PMID: 27330315 PMCID: PMC4898410 DOI: 10.2147/ott.s101628] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION Interleukin-10 (IL-10) is a multifactorial cytokine with a complex biological role in breast cancer. The aims of this study were to investigate any association between IL-10 gene promoter polymorphisms, 1082A>/G, -819T>C, and -592A>C, or haplotypes and breast cancer risk among Jordanian women and to evaluate any association between the most common haplotype with clinicopathological features of breast cancer. PATIENTS AND METHODS A total of 202 breast cancer patients and 210 age-matched healthy control subjects were genotyped for -1082A/G, -819T/C, and -592A/C single nucleotide polymorphisms in the promoter region of the IL-10 gene by polymerase chain reaction-restriction fragment length polymorphism. Study patients and control subjects were recruited from Prince Hamzah Hospital, Amman, Jordan (2012-2013). Ethical approval and signed consent forms were signed by all participants. DNA was extracted, and polymerase chain reaction fragments were amplified and restriction digested by MnII, MaeIII, and RsaI. RESULTS This study showed no statistically significant difference between -1082A/G, -819T/C, and -592A/C IL-10 genotypes or alleles among breast cancer patients or controls. Four different haplotypes ATA, ACC, GTA, and ACA within the IL-10 promoter gene were determined among both breast cancer and control groups. The most frequent haplotype was ACC among breast cancer patients and controls (41.6% and 40.7%, respectively). No statistical differences in these haplotypes among breast cancer patients or controls were determined. Analysis of the most common ACC haplotype showed statistical difference in positive estrogen receptor (P=0.022), positive progesterone receptor (P=0.004), cancer grade (P=0.0001), and cancer stage (P=0.009) among the ACC haplotype compared to non-ACC haplotype. CONCLUSION To our knowledge, this is the first report studying the association of IL-10 haplotype with breast cancer risk events among Jordanian females. The most frequent IL-10 haplotype among Jordanian breast cancer females is ACC haplotype. Patients carrying the ACC haplotype are associated with higher positive estrogen and progesterone receptors and advanced breast cancer grade and stage. These patients also had lower survival rate in the Kaplan-Meier survival plot compared to those with non-ACC haplotype.
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Affiliation(s)
- Manar Fayiz Atoum
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan
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Gupta S, Mehndiratta M, Kalra S, Kalra OP, Shukla R, Gambhir JK. Association of tumor necrosis factor (TNF) promoter polymorphisms with plasma TNF-α levels and susceptibility to diabetic nephropathy in North Indian population. J Diabetes Complications 2015; 29:338-42. [PMID: 25704106 DOI: 10.1016/j.jdiacomp.2015.01.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/09/2014] [Accepted: 01/05/2015] [Indexed: 12/11/2022]
Abstract
AIM The concept of diabetic nephropathy (DN) as a metabolic disease is now being replaced by chronic low-grade inflammatory disease. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine which plays an important role in the pathogenesis and clinical outcome of DN. Therefore, this work was planned to evaluate the association of -863C/A (rs1800630) and -1031T/C (rs1799964) polymorphisms in TNF gene with plasma TNF-α levels and DN among subjects with type 2 diabetes (T2DM) in a population from North India. METHODS Age and sex matched 100 healthy controls (HC), 100 T2DM subjects without nephropathy (DM) and 100 subjects with DN were screened for above polymorphisms using the PCR-RFLP methods. Plasma TNF-α levels were measured by ELISA. Analysis of variance and logistic regression were used to associate individual polymorphisms with plasma TNF-α levels and DN. RESULTS The allelic frequencies of -863C/A were 0.86/0.14 in HC, 0.72/0.23 in DM and 0.84/0.16 in DN, and that of -1031T/C were 0.89/0.11 in HC, 0.95/0.05 in DM and 0.80/0.20 in DN. The carriers of -863A allele had significantly lower plasma TNF-α levels (p<0.05). The -863C/A (OR=0.439, 95% CI=0.244-0.789, p=0.006) and -1031T/C (OR=3.0, 95% CI=1.355-6.642, p=0.007) were strongly associated with risk of development of DN. CONCLUSIONS -863C/A was associated with low whereas -1031T/C with high TNF-α levels. The, results suggest that -863C/A polymorphism might be protective whereas -1031T/C may be associated with increased risk for DN in subjects with T2DM from North India.
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Affiliation(s)
- Stuti Gupta
- Molecular Diagnostic Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India
| | - Mohit Mehndiratta
- Molecular Diagnostic Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India
| | - Sarathi Kalra
- Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India
| | - Om P Kalra
- Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India
| | - Rimi Shukla
- Molecular Diagnostic Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India
| | - Jasvinder K Gambhir
- Molecular Diagnostic Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
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Dubé PE, Punit S, Polk DB. Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2015; 308:G161-70. [PMID: 25477373 PMCID: PMC4312954 DOI: 10.1152/ajpgi.00142.2014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are major therapeutic targets for inflammatory bowel disease. Research advances have demonstrated that TNF produces pleiotropic responses in the gastrointestinal (GI) tract. Although in excess TNF can contribute to GI pathology, TNF is also a critical protective factor to promote GI homeostasis following injury and inflammation. Genetic studies using candidate and genome-wide association study approaches have identified variants in TNF or its receptors that are associated with Crohn's disease or ulcerative colitis in multiple populations, although the basis for these associations remains unclear. This review considers the efficacy and mechanism of anti-TNF therapies for inflammatory bowel disease to reconcile the many disparate aspects of TNF research and to consider the potential protective effects of TNF signaling in GI health.
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Affiliation(s)
- Philip E. Dubé
- 1Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California; and
| | - Shivesh Punit
- 1Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California; and
| | - D. Brent Polk
- 1Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California; and ,3Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California
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The effect of turmeric (Curcuma longa) extract on the functionality of the solute carrier protein 22 A4 (SLC22A4) and interleukin-10 (IL-10) variants associated with inflammatory bowel disease. Nutrients 2014; 6:4178-90. [PMID: 25314644 PMCID: PMC4210912 DOI: 10.3390/nu6104178] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 09/09/2014] [Accepted: 09/29/2014] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual's capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae) has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152) and interleukin-10 (IL-10, rs1800896) associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene promoter activity (IL-10, -1082A). The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions.
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Wouters MM, Lambrechts D, Becker J, Cleynen I, Tack J, Vigo AG, Ruiz de León A, Urcelay E, Pérez de la Serna J, Rohof W, Annese V, Latiano A, Palmieri O, Mattheisen M, Mueller M, Lang H, Fumagalli U, Laghi L, Zaninotto G, Cuomo R, Sarnelli G, Nöthen MM, Vermeire S, Knapp M, Gockel I, Schumacher J, Boeckxstaens GE. Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia. Gut 2014; 63:1401-1409. [PMID: 24259423 DOI: 10.1136/gutjnl-2013-304848] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. METHODS 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. RESULTS The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. CONCLUSIONS Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.
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Affiliation(s)
- Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium
| | - Jessica Becker
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Isabelle Cleynen
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Ana G Vigo
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Antonio Ruiz de León
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Elena Urcelay
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Julio Pérez de la Serna
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Wout Rohof
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Vito Annese
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Anna Latiano
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Manuel Mattheisen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany Institute for Genomic Mathematics, University of Bonn, Bonn, Germany Department of Biostatistics, Harvard School of Public Health, Boston, USA
| | - Michaela Mueller
- Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Uberto Fumagalli
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Luigi Laghi
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Giovanni Zaninotto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Giovanni Sarnelli
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Markus M Nöthen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Ines Gockel
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Johannes Schumacher
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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NADERI N, FARNOOD A, DADAEI T, HABIBI M, BALAII H, FIROUZI F, MAHBAN A, SOLTANI M, ZALI M. Association of Tumor Necrosis Factor Alpha Gene Polymorphisms with Inflammatory Bowel Disease in Iran. IRANIAN JOURNAL OF PUBLIC HEALTH 2014; 43:630-6. [PMID: 26060764 PMCID: PMC4449411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 02/22/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology, in which genetic factors, seem to play an important role in the disease predisposition and course. Assessment of tumor necrosis factor (TNF-α) gene polymorphisms in many populations showed a possible association with IBD. Considering the genetic variety in different ethnic groups, the aim of the present study was to investigate the association of five important single nucleo-tide polymorphisms (SNPs) in the promoter region of (TNF-α) gene with IBD in Iran. METHODS In this case-control study, 156 Ulcerative colitis (UC) patients, 50 Crohn's disease (CD) patients and 200 sex and age matched healthy controls of Iranian origin were enrolled. The study was performed during a two year period (2008-2010) at Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. DNA samples were evaluated for (TNF-α) gene polymorphisms (including -1031, -863, -857, -308 and -238) by PCR and RFLP methods. RESULTS The frequency of the mutant allele of -1031 polymorphism was significantly higher in Iranian patients with Crohn's disease compared to healthy controls (P=0.01, OR=1.92; 95% CI: 1.14-3.23). None of the other evaluated polymorphisms demonstrated a significant higher frequency of mutant alleles in Iranian IBD patients compared to controls. CONCLUSION Among the five assessed (SNPs), only -1031 polymorphism of (TNF-α) gene may play a role in disease susceptibility for Crohn's disease in Iran. This pattern of distribution of (TNF-α) gene polymorphisms could be specific in this population.
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Affiliation(s)
- Nosratollah NADERI
- 1. Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Alma FARNOOD
- 2. Imam Khomeini Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Tahereh DADAEI
- 1. Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran,* Corresponding Author:
| | - Manijeh HABIBI
- 1. Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Hedie BALAII
- 2. Imam Khomeini Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Farzad FIROUZI
- 1. Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | | | - Masoumeh SOLTANI
- 1. Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Mohammadreza ZALI
- 1. Gastroenterology and Liver Disease Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
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Magyari L, Kovesdi E, Sarlos P, Javorhazy A, Sumegi K, Melegh B. Interleukin and interleukin receptor gene polymorphisms in inflammatory bowel diseases susceptibility. World J Gastroenterol 2014; 20:3208-22. [PMID: 24695754 PMCID: PMC3964393 DOI: 10.3748/wjg.v20.i12.3208] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), represents a group of chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Genetic markers are associated with disease phenotype and long-term evolution, but their value in everyday clinical practice is limited at the moment. IBD has a clear immunological background and interleukins play key role in the process. Almost 130 original papers were revised including meta-analysis. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but text often do not available for the doctors use these in the clinical practice nowadays. We conducted a systematic review of the current literature on interleukin and interleukin receptor gene polymorphisms associated with IBD, performing an electronic search of PubMed Database from publications of the last 10 years, and used the following medical subject heading terms and/or text words: IBD, CD, UC, interleukins and polymorphisms.
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Lv H, Jiang Y, Li J, Zhang M, Shang Z, Zheng J, Wu X, Liu P, Zhang R, Yu H. Association between polymorphisms in the promoter region of interleukin-10 and susceptibility to inflammatory bowel disease. Mol Biol Rep 2014; 41:1299-310. [PMID: 24407599 DOI: 10.1007/s11033-013-2975-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 12/24/2013] [Indexed: 12/19/2022]
Abstract
The aim of this study was to assess the association of polymorphisms in the promoter region of the IL-10 gene with the risk of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Fifteen studies (3,693 cases and 4,574 controls) were included in a meta-analysis of association between IL-10 -1082G/A, -819C/T and -592C/A polymorphisms, and IBD, CD and UC using allele contrast and the recessive, dominant, and additive models. Hardy-Weinberg equilibrium was confirmed for each study. Heterogeneity and study quality were investigated using stratification analyses and sensitivity analyses. Polymorphism -1082G/A showed significant association with CD, with odds ratios (ORs) for the GG + GA genotype and GG versus AA genotype of 1.278 (1.004-1.627) and 1.238 (1.027-1.492) in all subjects. Significant associations were found in the Caucasian subgroup using the allele contrast, dominant, and additive models. C-allele carriers of the -819C/T polymorphism were at increased risk of IBD (OR 1.093, 95% CI 1.004-1.190). Association with the -819C/T polymorphism was also found in Caucasians with CD (C vs. T: OR 1.104, 95% CI 1.010-1.206; CC + CT vs. TT: OR 1.328, 95% CI 1.006-1.754; CC vs. TT: OR 1.339, 95% CI 1.008-1.778), and with UC (CC vs. CT + TT: OR 1.188, 95% CI 1.019-1.385). No significant association was found between the -592C/A polymorphism and IBD, CD or UC. In conclusion, the meta-analysis demonstrated clear association between the IL-10 polymorphisms -1082G/A and -819C/T and the risk of IBD.
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Affiliation(s)
- Hongchao Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, People's Republic of China
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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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Shouval DS, Ouahed J, Biswas A, Goettel JA, Horwitz BH, Klein C, Muise AM, Snapper SB. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. Adv Immunol 2014; 122:177-210. [PMID: 24507158 PMCID: PMC4741283 DOI: 10.1016/b978-0-12-800267-4.00005-5] [Citation(s) in RCA: 231] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interleukin 10 (IL10) is a key anti-inflammatory cytokine that can inhibit proinflammatory responses of both innate and adaptive immune cells. An association between IL10 and intestinal mucosal homeostasis became clear with the discovery that IL10 and IL10 receptor (IL10R)-deficient mice develop spontaneous intestinal inflammation. Similarly, patients with deleterious mutations in IL10, IL10RA, or IL10RB present with severe enterocolitis within the first months of life. Here, we review recent findings on how IL10- and IL10R-dependent signaling modulates innate and adaptive immune responses in the murine gastrointestinal tract, with implications of their role in the prevention of inflammatory bowel disease (IBD). In addition, we discuss the impact of IL10 and IL10R signaling defects in humans and their relationship to very early-onset IBD (VEO-IBD).
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Affiliation(s)
- Dror S Shouval
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jodie Ouahed
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Amlan Biswas
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jeremy A Goettel
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bruce H Horwitz
- Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Christoph Klein
- Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
| | - Aleixo M Muise
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada; Program in Cell Biology at University of Toronto, Toronto, Ontario, Canada
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Gastroenterology, Brigham & Women's Hospital, Boston, Massachusetts, USA.
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Engelhardt KR, Grimbacher B. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Curr Top Microbiol Immunol 2014; 380:1-18. [PMID: 25004811 DOI: 10.1007/978-3-662-43492-5_1] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) represents a heterogeneous group of gastrointestinal disorders, where commensal gut flora provokes an either (a) insufficient or (b) uncontrolled immune response. This results either in a lack of or in excessive inflammation mainly manifesting as Crohn's disease or ulcerative colitis. IBD commonly presents in adolescence and adulthood and often follows a chronic relapsing course. Genetic and/or environmental factors contribute to the failure of gut immune homeostasis. Genome-wide association studies have identified over 160 susceptibility loci associated with IBD, including polymorphisms in interleukin-10 (IL-10). The anti-inflammatory cytokine IL-10 dampens intestinal inflammation and is therefore a good candidate gene for IBD. Polymorphisms in the IL-10 receptor are also associated with ulcerative colitis presenting in early childhood. Moreover, severe infantile enterocolitis resembling Crohn's disease, caused by loss-of-function mutations in IL-10 and IL-10 receptor, is characterised by a very early onset (usually within the first 3 months of life), unresponsiveness to standard treatment including immunosuppressive therapy, and severe perianal disease with abscesses and fistulas. In these patients, inflammation and polymorphic infiltrates are mainly confined to the colon with very little involvement of the small intestine. Ulceration and granulomas, bloody diarrhoea and failure to thrive also occur. Furthermore, patients may suffer from recurrent fever and respiratory infections. Individuals with IL-10 receptor mutations also experience cutaneous folliculitis and arthritis. Hematopoietic stem cell transplantation is currently the only curative therapy.
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Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J 2013; 54:201-5. [PMID: 23624446 DOI: 10.11622/smedj.2013073] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION This study examined the characteristics and trends in the incidence of inflammatory bowel disease (IBD) among children in Singapore. METHODS We retrospectively reviewed all patients under 18 years diagnosed with IBD over a 14-year period. Information on demographics, disease presentation, laboratory findings, radiological investigations, and endoscopic and histological findings were obtained from the patients' medical records. RESULTS 32 patients were diagnosed with IBD, 30 of whom had Crohn's disease and 2 had ulcerative colitis. The incidence of IBD rose from an initial rate of 2.2 per 100,000 patients in the year 2000 to a peak of 11.4 patients per 100,000 patients by 2008. Median age of onset of symptoms was 10.5 years. There were more boys (63%) than girls in the group and a higher representation of Indians (34.4%). The most common presenting symptoms were abdominal pain (87.5%), diarrhoea (75.0%) and weight loss (71.9%). Extraintestinal manifestations such as fever and arthralgia were found in over 50% of patients. The most common physical findings were perianal abnormalities (56.3%), mouth ulcers (37.5%) and growth failure (15.6%). Abnormal laboratory findings such as low albumin, raised erythrocyte sedimentation rate, anaemia, thrombocytosis and high C-reactive protein were found in nearly half of the patients. Endoscopic and histological findings showed that a majority of patients (90.6%) also had evidence of inflammation in the upper gastrointestinal tract. CONCLUSION Paediatric IBD is on the rise. The higher occurrence in Indians, earlier onset and more florid presentation may suggest different genetic and environmental influences specific to Asian children.
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Affiliation(s)
- Hui Ping Chu
- Raffles Children's Centre, 585 North Bridge Road, #12-00 Raffles Hospital, Singapore.
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27
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Zou L, Wang L, Gong X, Zhao H, Jiang A, Zheng S. The association between three promoter polymorphisms of IL-10 and inflammatory bowel diseases (IBD): a meta-analysis. Autoimmunity 2013; 47:27-39. [PMID: 24128120 DOI: 10.3109/08916934.2013.843672] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
AIM To assess the relationship of the Interleukin-10 (IL-10) -1082G/A (rs1800896), -819C/T (rs1800871) and -592C/A (rs1800872) polymorphism with inflammatory bowel disease (IBD) by means of meta-analysis. METHODS Published data addressing the association between polymorphism of the IL-10 with Crohn's disease (CD) and Ulcerative colitis (UC) were selected from electronic databases. A total of 17 studies including 4132 cases and 5109 controls were included in this meta-analysis which detected whether -1082G/A, -819C/T and -592C/A polymorphism were associated with CD or UC susceptibility. RESULT The IL-10 -819C/T and -519C/A variant allele observed a significant association with UC (OR 1.16, 95%CI 1.03-1.31 and OR 1.19, 95%CI 1.03-1.38) not CD while there is no significant association between -1082G/A and UC or CD. CONCLUSION The IL-10 -819C/T and -592C/A polymorphisms contribute to susceptibility to UC, but IL-10 -1082G/A polymorphism neither associated with CD nor UC.
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Affiliation(s)
- Liwei Zou
- Department of Radiology, The Second Hospital of Anhui Medical University , Hefei, Anhui Province , China
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Williamson DM, Marrie RA, Ashley-Koch A, Satten GA. Interaction of HLA-DRB1* 1501 and TNF-Alpha in a Population-based Case-control Study of Multiple Sclerosis. ACTA ACUST UNITED AC 2013; 1:10-17. [PMID: 25741530 DOI: 10.13189/iid.2013.010102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This study was conducted to determine whether single nucleotide polymorphisms (SNPs) in nine genes (human leukocyte antigen (HLA), T cell receptor beta (TCA receptor β), tumor necrosis factor α (TNF α), tumor necrosis factor β (TNF β), apolipoprotein E (APOE), interleukin 7 receptor alpha chain (IL7RA) interleukin 2 receptor alpha chain (IL2RA) myelin basic protein (MBP) and vitamin D receptor (VDR)) associated with multiple sclerosis (MS) could be replicated in a population-based sample, and to determine if these associations are modified by presence of HLA DRB1*1501. DNA was available from 722 individuals (223 with MS and 499 controls) who participated in a population-based case-control study. Cases and controls were matched on ancestry, age, gender and geographic area. HLA DRB1*1501 risk allele (T) was confirmed in this population using a genotypic test, controlling for multiple comparisons. Examining the effect of each SNP in the presence or absence of the HLA DRB1*1501 risk allele identified significant associations with TNF α -1031 (rs1799964) among those without the HLA risk allele. No additional interactions were significant in a cases-only analysis. Our results indicate that an interaction between SNPs in TNF α and HLA DRB1*1501 may influence the risk of developing MS.
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Affiliation(s)
- Dhelia M Williamson
- Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, 30333, United States
| | - Ruth Ann Marrie
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1R9
| | - Allison Ashley-Koch
- Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, 27710, United States
| | - Glen A Satten
- Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, 30333, United States
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Merino AM, Zhang K, Kaslow RA, Aissani B. Structure of tumor necrosis factor-alpha haploblocks in European populations. Immunogenetics 2013; 65:543-52. [PMID: 23579626 PMCID: PMC3985396 DOI: 10.1007/s00251-013-0700-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 03/23/2013] [Indexed: 10/27/2022]
Abstract
DNA variants in the tumor necrosis factor-α (TNF) and linked lymphotoxin-α genes, and specific alleles of the highly polymorphic human leukocyte antigen B (HLA-B) gene have been implicated in a plethora of immune and infectious diseases. However, the tight linkage disequilibrium characterizing the central region of the human major histocompatibility complex (MHC) containing these gene loci has made difficult the unequivocal interpretation of genetic association data. To alleviate these difficulties and facilitate the design of more focused follow-up studies, we investigated the structure and distribution of HLA-B-specific MHC haplotypes reconstructed in a European population from unphased genotypes at a set of 25 single nucleotide polymorphism sites spanning a 66-kilobase long region across TNF. Consistent with the published data, we found limited genetic diversity across the so-called TNF block, with the emergence of seven common MHC haplotypes, termed TNF block super-haplotypes. We also found that the ancestral haplotype 8.1 shares a TNF block haplotype with HLA-B*4402. HLA-B*5701, a known protective allele in HIV-1 pathogenesis, occurred in a unique TNF block haplotype.
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Affiliation(s)
| | - Kui Zhang
- Department of Biostatistics, University of Alabama at Birmingham
| | - Richard A. Kaslow
- Department of Epidemiology, University of Alabama at Birmingham
- Department of Medicine, University of Alabama at Birmingham
| | - Brahim Aissani
- Department of Epidemiology, University of Alabama at Birmingham
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Fürst D, Zollikofer C, Schrezenmeier H, Mytilineos J. TNFA promoter alleles--frequencies and linkage with classical HLA genes in a South German Caucasian population. ACTA ACUST UNITED AC 2013; 80:502-8. [PMID: 23137321 DOI: 10.1111/tan.12025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The tumor necrosis factor alpha (TNFA) promoter region exhibits several polymorphisms, which have been hypothesized to influence gene expression, thereby associating positively or negatively with inflammatory conditions. Many studies have focused on single nucleotide polymorphisms (SNPs) taking not into account additive or inverse effects between different SNPs. We typed 1,021 healthy Caucasian volunteer stem cell donors for their TNFA promoter as well as their HLA-A,-C,-B,-DRB1 loci. Using statistical methods, we reconstructed TNFA promoter alleles and analyzed their frequency and linkage with HLA genes. We show that the number of TNFA promoter alleles frequent enough to be analyzed in clinical studies is limited and that a strong linkage with classical HLA genes is present, especially for the extended HLA-haplotype HLA-A*01:01/HLA-C*07:01/HLA-B*08:01/TNFA promoter allele 3/HLA*DRB1*03:01. Taking into account SNP frequency information, it is possible to quite accurately deduce TNFA promoter alleles by generic Sanger sequencing, obviating the need for elaborating allele-specific sequencing. This information may enable investigators to consider the complete TNFA regulatory region in a phase-separated manner in contrast to previous approaches examining only one or few isolated SNPs.
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Affiliation(s)
- D Fürst
- Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, Ulm, Germany.
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Eipel OT, Németh K, Török D, Csordás K, Hegyi M, Ponyi A, Ferenczy A, Erdélyi DJ, Csóka M, Kovács GT. The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy. Int J Hematol 2013; 97:216-22. [DOI: 10.1007/s12185-012-1236-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 11/28/2012] [Accepted: 11/28/2012] [Indexed: 11/27/2022]
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Tan SY, Wu PB, Zhang G, Luo HS, Ye HL. Association between interleukin-10-819 promoter polymorphism and susceptibility to Crohn's disease: A meta-analysis. Shijie Huaren Xiaohua Zazhi 2012; 20:3603-3608. [DOI: 10.11569/wcjd.v20.i35.3603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the association between interleukin-10 (IL-10) 819T/C polymorphism and Crohn's disease susceptibility.
METHODS: A systematic search of electronic databases such as CBM, CNKI, PubMed, Elsevier and EMbase was performed to retrieve relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated using the RevMan 5.1.4 software, and publication bias was tested by Egger's regression test and Begg's test.
RESULTS: A total of 11 studies involving 1670 patients with Crohn's disease and 3312 healthy controls were identified. The results of meta-analyses showed no significant association between IL-10 819T/C polymorphism and susceptibility to Crohn's disease (for T/T vs C/C: OR = 0.90, 95% CI: 0.70 to 1.17; T/C vs C/C: OR = 0.84, 95% CI: 0.56 to 1.27; for dominant inheritance model: OR = 0.97, 95% CI 0.86 to 1.10; for recessive inheritance model: OR = 0.90, 95% CI: 0.71 to 1.14).
CONCLUSION: Current evidence strongly suggests that there is no significant association between IL-10 819T/C polymorphism and susceptibility to Crohn's disease.
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Zhu H, Lei X, Liu Q, Wang Y. Interleukin-10-1082A/G polymorphism and inflammatory bowel disease susceptibility: a meta-analysis based on 17,585 subjects. Cytokine 2012; 61:146-53. [PMID: 23046617 DOI: 10.1016/j.cyto.2012.09.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 09/06/2012] [Accepted: 09/17/2012] [Indexed: 12/19/2022]
Abstract
A large number of studies have shown that the interleukin-10 (IL-10)-1082A/G polymorphism is implicated in susceptibility to inflammatory bowel disease (IBD). However, the results are inconsistent. We performed this meta-analysis to estimate the association between -1082A/G polymorphism in the IL-10 gene and IBD susceptibility. A total number of 18 case-control studies including 17,585 subjects were identified. No association was found between -1082A/G polymorphism and ulcerative colitis (UC) susceptibility. However, increased risk of Crohn's disease (CD) was associated with -1082A/G polymorphism in the dominant genetic model (GG+GA vs. AA: OR=1.22, 95% CI: 1.02-1.46, P=0.028) and the heterozygote comparison (GA vs. AA: OR=1.28, 95% CI: 1.05-1.55, P=0.015). The results of this meta-analysis provide evidence for the association between IL-10-1082A/G polymorphism and susceptibility of CD. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future.
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Affiliation(s)
- Hang Zhu
- Maternal and Child Hygiene Department, School of Public Health and Management, Chongqing Medical University, China
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Abstract
Glucocorticoid therapy is used in the treatment of moderate to severe inflammatory bowel disease (IBD). However, IBD patients display varying degrees of glucocorticoid sensitivity: some respond rapidly to the given treatment, whereas others show no response, or develop steroid therapy-related side-effects. At present, we cannot foresee whether the patient will benefit from the administered glucocorticoids or not. During the past 10 years, numerous attempts have been made to provide the means to identify and predict steroid therapy-sensitive patients in advance. This would be vital to avoid unnecessary glucocorticoid exposure in patients that do not respond to treatment with steroids. Here we provide a concise review of recent developments regarding the molecular basis of glucocorticoid sensitivity in IBD patients and the methods employed to assess it.
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Affiliation(s)
- Marianne Sidoroff
- Hospital for Children and Adolescents, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
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Xie C, Liu XF, Yang MS. A meta-analysis on the association between three promoter variants of TNF-α and Crohn's disease. Mol Biol Rep 2012; 39:1575-1583. [PMID: 21633892 DOI: 10.1007/s11033-011-0896-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Accepted: 05/17/2011] [Indexed: 01/22/2023]
Abstract
Tumor necrosis factor-alpha (TNF-α) has been regarded as a candidate gene for Crohn's disease (CD) based on its inflammatory function in immune reaction and the clinical effectiveness of anti-TNF-α therapy. However, studies to date have reported inconsistent findings for the association between TNF-α and CD. The PubMed, EMBASE, and Medline databases were systematically reviewed from all English language publications up to April, 2011. A total of twenty-nine studies concerning the association between CD and the TNF-α promoter polymorphisms of -308G/A, -857C/T and -238G/A were identified, among of them only twenty-three studies match the inclusion criteria (including 3,843 cases and 6,260 controls) and were selected for the statistical test. We found that neither the G allele of -308G/A (OR 1.02, 95% CI 0.87-1.19, P = 0.84), C allele of -857C/T (OR 0.97, 95% CI 0.86-1.09, P = 0.57) and G allele of -238G/A (OR 0.91, 95% CI 0.70-1.18, P = 0.48), and nor their GG (OR 1.05, 95% CI 0.88-1.25, P = 0.59), CC (OR 0.98, 95% CI 0.86-1.12, P = 0.76) and GG (OR 0.92, 95% CI 0.70-1.21, P = 0.55) genotypes were associated with CD susceptibility, respectively. Our meta-analysis demonstrates that three promoter polymorphisms of TNF-α above may not confer susceptibility to CD.
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Affiliation(s)
- Cui Xie
- Laboratory of Disorder Genes and Department of Pharmacology, College of Pharmacy, Chongqing Medical University, 1 Yi Xue Yuan Road, P. O. Box 380, Chongqing 400016, People's Republic of China
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2012; 18:105-18. [PMID: 22253516 PMCID: PMC3257437 DOI: 10.3748/wjg.v18.i2.105] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 04/25/2011] [Accepted: 05/02/2011] [Indexed: 02/06/2023] Open
Abstract
Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2011; 17:5246-59. [PMID: 22219593 PMCID: PMC3247688 DOI: 10.3748/wjg.v17.i48.5246] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Considering the epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have so far been related to the diagnosis of Crohn's disease. These genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the strongest and most replicated associations with Crohn's disease have been demonstrated with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in the prognosis of Crohn's disease and many attempts have been made for classification of genetic profiles in Crohn's disease. CARD15 seems to be not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding of Crohn's disease genetics is of value, but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Hofmann SR, Schwarz T, Möller JC, Morbach H, Schnabel A, Rösen-Wolff A, Girschick HJ, Hedrich CM. Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression. Clin Immunol 2011; 141:317-27. [PMID: 21925952 DOI: 10.1016/j.clim.2011.08.012] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 08/19/2011] [Accepted: 08/21/2011] [Indexed: 11/30/2022]
Abstract
Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced (p<0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.
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Affiliation(s)
- S R Hofmann
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, D-01307 Dresden, Germany
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Begue B, Verdier J, Rieux-Laucat F, Goulet O, Morali A, Canioni D, Hugot JP, Daussy C, Verkarre V, Pigneur B, Fischer A, Klein C, Cerf-Bensussan N, Ruemmele FM. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol 2011; 106:1544-55. [PMID: 21519361 DOI: 10.1038/ajg.2011.112] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Early onset inflammatory bowel diseases (EO-IBD) developing during the first year of life are likely to reflect inherited defects in key mechanism(s) controlling intestinal homeostasis, as recently suggested for interleukin 10 (IL10). Thus, we aimed to further elaborate the hypothesis of defective anti-inflammatory responses in patients with IBD. METHODS The capacities of transforming growth factor β (TGFβ) and IL10 to inhibit proinflammatory cytokine production by monocyte-derived dendritic cells (MoDC) or peripheral blood cells (PBMC) was analyzed in 75 children with IBD, including 13 infants with EO-IBD (in whom autoimmune diseases or classical immunodeficiencies were ruled out). IL10 receptor-A/-B expression, STAT3 activation in response to IL6, IL10, IL21, IL22 were analyzed by FACS and western blotting. IL10RA and B genes were sequenced. The response to IL22 was tested in ileal/colonic tissue cultures. Tissue gene expression was analyzed by Taqman real-time polymerase chain reaction. RESULTS Production of IL10 in response to bacterial motifs was normal in all IBD patients. In contrast to our original hypothesis, no defect of the anti-inflammatory potential of TGFβ and IL10 was observed in children with IBD or EO-IBD except two infants who presented with granuloma-positive colitis at 3 months of life: no response to IL10 was observed secondary to mutations in the α (p.R262C) or β (p.E141X) chain of IL10R, respectively, although a fully functional Jak-STAT3 pathway was present in both patients. When analyzing the regulation of intestinal bacterial clearance, we detected a defect in the patient with absent IL10 RB to upregulate protective transcripts in response to IL22, whereas all other EO-IBD patients, including the patient with an abnormal α chain, responded normally. CONCLUSIONS Impaired IL10 signaling characterizes a subgroup of IBD patients, whereas the majority of children with severe IBD including EO forms normally produces and responds to IL10. Defective IL22 signaling may additionally impair intestinal epithelial clearance. Our data point out the complexity of IBD, which represent a group of distinct diseases with several pathogenetic abnormalities.
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The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population. Hum Immunol 2011; 72:431-5. [PMID: 21354456 DOI: 10.1016/j.humimm.2011.02.014] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 02/10/2011] [Accepted: 02/22/2011] [Indexed: 12/13/2022]
Abstract
Interleukin (IL)-10 has important effects in immunoregulation and inflammation, and previous studies have provided evidence for the involvement of IL-10 in the pathogenesis of Crohn's disease (CD). In this study, we investigated whether genetic variants of the IL-10 gene were associated with CD in a New Zealand population. Three single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 (rs1800871, rs1800872, and rs1800896) and a flanking SNP, rs3024505, were genotyped in a well-characterized New Zealand dataset consisting of 342 CD cases and 610 controls. Furthermore, we measured serum IL-10 levels in a number of the CD patients and controls and examined whether a relationship existed between these polymorphisms and serum IL-10 levels. We demonstrated an association with CD for SNPs rs3024505 and rs1800896, and phenotypic analysis indicated an association of rs3024505 with an early age at first diagnosis, stricturing CD behavior, and requirement for bowel resection. We also observed that IL-10 concentration was significantly higher in CD patients than in the controls and that the T allele of rs1800896, the A allele of rs1800871, and the T allele of rs1800872 were associated with increased serum IL-10 levels.
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Gu QP, Bai AP. Interleukin-10 and inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2011; 19:57-61. [DOI: 10.11569/wcjd.v19.i1.57] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The etiology of inflammatory bowel disease (IBD) has not been fully elucidated. Evidence indicates that dysregulation of intestinal mucosal immunity plays a critical role in the pathogenesis of IBD since it can cause overproduction of inflammatory cytokines and lead to uncontrolled intestinal inflammation. Cytokines play a pivotal role in modulating inflammation and may therefore be a good target for IBD therapy. Interleukin-10 (IL-10) is a regulatory cytokine which inhibits both antigen presentation and subsequent pro-inflammatory cytokine release and has been proposed as a potent anti-inflammatory biological therapy for chronic IBD. Many IL-10-based strategies have been developed for treatment of IBD, including recombinant IL-10, genetically modified bacteria expressing IL-10, adenoviral vectors encoding IL-10, and combination therapy with IL-10 and Treg cells. The use of IL-10-based strategies will provide new insights into cell- and gene-based treatment for IBD.
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Liang WB, Lv ML, Su XW, Gao LB, Fang WL, Luo HB, Zhang L. Association of tumor necrosis factor gene polymorphisms with susceptibility to dilated cardiomyopathy in a Han Chinese population. DNA Cell Biol 2010; 29:625-8. [PMID: 20491592 DOI: 10.1089/dna.2010.1044] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Tumor necrosis factor (TNF) is an immunomodulatory cytokine that plays an important role in many inflammatory and autoimmune diseases. We investigated the correlation between single-nucleotide polymorphisms of the TNF gene [i.e., TNF-α (308), TNF-α (857), TNF-α (863), TNF-α (1031), and TNF-ß (+252)] and dilated cardiomyopathy (DCM). A total of 110 DCM patients and 110 control subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism and DNA-sequencing assay. GA=AA genotypes of TNF-α (308) were significantly associated with increased risk of DCM compared with GG genotype (odds ratio[OR]=1.92; 95% confidence intervals [CI], 1.05-3.52). Similarly, GA=AA of TNF-ß (+252) was significantly associated with increased risk of DCM compared with GG genotype (OR=1.97; 95% CI, 1.14-3.38). Additionally, A allele of TNF-α (-308) and TNF-ß (+252) was associated with a 1.76-fold increased risk of DCM compared with G allele (OR=1.76; 95% CI, 1.05-2.95 and OR=1.79; 95% CI, 1.22-2.63, respectively). However,no association between DCM and TNF-α (857), TNF-α (1031), and TNF-α (863) was observed. TNF gene polymorphisms may be associated with risk of DCM.
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Affiliation(s)
- Wei-Bo Liang
- Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China
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Mwinyi J, Wenger C, Eloranta JJ, Kullak-Ublick GA. Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients. World J Gastroenterol 2010; 16:3888-96. [PMID: 20712049 PMCID: PMC2923762 DOI: 10.3748/wjg.v16.i31.3888] [Citation(s) in RCA: 18] [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
AIM: To study whether the glucocorticoid receptor (GR/NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD).
METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes.
RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically significant association with glucocorticoid therapy success.
CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome.
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Abstract
PURPOSE OF REVIEW Inflammatory bowel diseases (IBD) comprise a heterogeneous group of distinct intestinal disorders. Here, we discuss the concept of childhood-onset IBD as separate disease forms within a larger multifactorial disease category. RECENT FINDINGS There are excellent epidemiological data indicating that the incidence of pediatric IBD, mainly Crohn's disease, is still increasing over the last decades, with indicators of more extensive and more severe disease presentations in children compared to adults, also reflected by higher levels of humoral immune responses. Recent genetic scans allowed to identify particular susceptibility genes for pediatric IBD forms, such as IL27 or probably DcR3. Early postnatal onset forms of IBD might reflect monogenetic causes, as suggested with the finding of IL10 signaling defects that may define a new form of IBD. SUMMARY There are good epidemiological, genetic and clinical data to distinguish different forms of IBD, particularly forms starting early in life. Profound insights in the molecular basis of immune dysregulation in IBD have been gained over the last few years. These recent discoveries will nourish and substantially stimulate the future search for precise cause(s) responsible for life-long intestinal inflammation and it will help to explain the still ongoing rise in incidence in childhood IBD.
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Deng L, Zhou JF, Sellers RS, Li JF, Nguyen AV, Wang Y, Orlofsky A, Liu Q, Hume DA, Pollard JW, Augenlicht L, Lin EY. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2010. [PMID: 20042677 DOI: 10.2353/ajpath.2010.090622.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Inflammatory bowel disease (IBD) is a high-risk condition for human colorectal cancer. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited. Here we established a novel mouse model of colitis-associated cancer by genetically inactivating signal transducer and activator of transcription 3 (Stat3) in macrophages, with partial deletion in other myeloid and lymphoid cells. Inflammation developed in the colon of mutant mice spontaneously, and tumor lesions, including invasive carcinoma, arose in the inflamed region of the intestine with a frequency similar to that observed in human IBD patients. The development of both inflammation and tumors in the mutant mice required the presence of microflora. Indeed, inflammation was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation, and activation of the mammalian target of rapamycin (mTOR)-Stat3 pathway in epithelial and tumor cells. The activation of this pathway was essential for both the excess proliferation of epithelial/tumor cells and the disruption of colonic homeostasis in the mutant mice. Notably, a similar abnormal up-regulation of mTOR-Stat3 signaling was consistently observed in the colonic epithelial cells of human IBD patients with active disease. These studies demonstrate a novel mouse model of IBD-colorectal cancer progression in which disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation are integrated and simultaneously linked to the development of malignancy.
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Affiliation(s)
- Lin Deng
- Department of Medicine, Oncology Division, Albert Einstein Cancer Center, Bronx, NY 10467, USA
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Deng L, Zhou JF, Sellers RS, Li JF, Nguyen AV, Wang Y, Orlofsky A, Liu Q, Hume DA, Pollard JW, Augenlicht L, Lin EY. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 176:952-67. [PMID: 20042677 DOI: 10.2353/ajpath.2010.090622] [Citation(s) in RCA: 175] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is a high-risk condition for human colorectal cancer. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited. Here we established a novel mouse model of colitis-associated cancer by genetically inactivating signal transducer and activator of transcription 3 (Stat3) in macrophages, with partial deletion in other myeloid and lymphoid cells. Inflammation developed in the colon of mutant mice spontaneously, and tumor lesions, including invasive carcinoma, arose in the inflamed region of the intestine with a frequency similar to that observed in human IBD patients. The development of both inflammation and tumors in the mutant mice required the presence of microflora. Indeed, inflammation was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation, and activation of the mammalian target of rapamycin (mTOR)-Stat3 pathway in epithelial and tumor cells. The activation of this pathway was essential for both the excess proliferation of epithelial/tumor cells and the disruption of colonic homeostasis in the mutant mice. Notably, a similar abnormal up-regulation of mTOR-Stat3 signaling was consistently observed in the colonic epithelial cells of human IBD patients with active disease. These studies demonstrate a novel mouse model of IBD-colorectal cancer progression in which disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation are integrated and simultaneously linked to the development of malignancy.
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Affiliation(s)
- Lin Deng
- Department of Medicine, Oncology Division, Albert Einstein Cancer Center, Bronx, NY 10467, USA
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