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Li H, Lai L, Shen J. Development of a susceptibility gene based novel predictive model for the diagnosis of ulcerative colitis using random forest and artificial neural network. Aging (Albany NY) 2020; 12:20471-20482. [PMID: 33099536 PMCID: PMC7655162 DOI: 10.18632/aging.103861] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis is a type of inflammatory bowel disease characterized by chronic and recurrent nonspecific inflammation of the intestinal tract. To find susceptibility genes and develop a novel predictive model of ulcerative colitis, two sets of cases and a control group containing the ulcerative colitis gene expression profile (training set GSE109142 and validation set GSE92415) were downloaded and used to identify differentially expressed genes. A total of 781 upregulated and 127 downregulated differentially expressed genes were identified in GSE109142. The random forest algorithm was introduced to determine 1 downregulated and 29 upregulated differentially expressed genes contributing highest to ulcerative colitis occurrence. Expression data of these 30 genes were transformed into gene expression scores, and an artificial neural network model was developed to calculate differentially expressed genes weights to ulcerative colitis. We established a universal molecular prognostic score (mPS) based on the expression data of the 30 genes and verified the mPS system with GSE92415. Prediction results agreed with that of an independent data set (ROC-AUC=0.9506/PR-AUC=0.9747). Our research creates a reliable predictive model for the diagnosis of ulcerative colitis, and provides an alternative marker panel for further research in disease early screening
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Affiliation(s)
- Hanyang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China.,Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Institute of Digestive Disease, Shanghai 200127, China
| | - Lijie Lai
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China.,Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Institute of Digestive Disease, Shanghai 200127, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China.,Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Institute of Digestive Disease, Shanghai 200127, China
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Yenmis G, Oner T, Cam C, Koc A, Kucuk OS, Yakicier MC, Dizman D, Kanigur Sultuybek G. Association of NFKB1 and NFKBIA polymorphisms in relation to susceptibility of Behçet's disease. Scand J Immunol 2015; 81:81-6. [PMID: 25367031 DOI: 10.1111/sji.12251] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 10/13/2014] [Indexed: 01/19/2023]
Abstract
Behçet's disease (BD) is a chronic inflammatory autoimmune disease. Although raised levels of proinflammatory cytokines in BD have been reported, the pathogenesis is still unknown. The aim of this study was to investigate the association of NFKB1 and NFKBIA polymorphisms and their single and combined analysis effects on susceptibility of BD in Turkish population. We analysed the distribution of NFKB1 -94 ins/del ATTG (rs28362491) and NFKBIA 3' UTR A→G (rs696) polymorphisms using PCR-RFLP method in 89 patients with BD and 190 controls in this population. Statistical analysis of the results was performed by calculating OR, and 95% CI via χ(2) test and using Bonferroni correction. According to the significant results of both single and combined genotype analysis, the frequencies of ins/ins genotype and ins allele of rs28362491 were significantly higher in patients with BD (Pc = 0.003, 0.004, respectively). Also, higher frequencies of the rs696 variant containing AA genotype was found in patients with BD (Pc = 0.0033), whereas no statistical significant differences in distribution of the alleles of rs696 polymorphism in patients and controls. In addition, according to the combined genotype analysis, the wild type of both rs28362491 and rs696 polymorphisms (ins/ins/AA genotype) was also significantly higher in BD cases (Pc = 0.044). Our findings prove that both single and combined genotype analysis of rs28362491 and rs696 polymorphisms indicate that the wild genotypes of both two SNPs (ins/ins and AA genotypes) and ins/ins/AA combined genotype are strongly associated with enhanced risk of BD in a Turkish population.
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Affiliation(s)
- G Yenmis
- Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
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Liu CE, Huang YH. PTPN2 and NF-κB single nucleotide polymorphisms associated with susceptibility to ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2015; 23:71-77. [DOI: 10.11569/wcjd.v23.i1.71] [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
Ulcerative colitis (UC) is a form of chronic and recurrent bowel disease with unknown etiology. Pieces of evidence suggest that UC should be evolved as a result of inappropriate and ongoing activation of the mucosal immune system driven by the luminal commensal microflora in a genetically susceptible host. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) and nuclear factor-kappa B (NF-κB) play important roles not only in inflammatory pathways, but also in the development of UC. In recent years, association of PTPN2 and NF-κB gene polymorphisms with susceptibility to UC has become a research focus in Western counties, but the studies are controversial in southern China. This paper reviews the PTPN2 and NF-κB gene single nucleotide poly-morphisms (SNPs) associated with susceptibility to UC.
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Polymorphism of the NFKB1 affects the serum inflammatory levels of IL-6 in Hashimoto thyroiditis in a Turkish population. Immunobiology 2014; 219:531-6. [DOI: 10.1016/j.imbio.2014.03.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 01/14/2014] [Accepted: 03/12/2014] [Indexed: 12/18/2022]
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Investigation of NF-κB1 and NF-κBIA gene polymorphism in non-small cell lung cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:530381. [PMID: 24707489 PMCID: PMC3953471 DOI: 10.1155/2014/530381] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Revised: 12/13/2013] [Accepted: 01/09/2014] [Indexed: 01/23/2023]
Abstract
Lung cancer is a complex, multifactorial disease which is the leading cause of cancer death in both men and women.
NF-κB is a transcription factor which is known to affect the expression of more than 150 genes related to inflammation, lymphocyte activation, cell proliferation, differentiation, and apoptosis, as well as contributing to cell apoptosis and survival. However, NF-κBIA (IκBα) is the inhibitor of the transcription factor. The -94ins/delATTG polymorphism of the NF-κB1 gene promoter region which causes a functional effect and NF-κBIA 3′UTR A → G polymorphism has been shown to be related to various inflammatory diseases and cancer. Ninety-five NSCLC patients and 99 healthy controls were included in study. The NF-κB1 -94ins/delATTG and NF-κBIA 3′UTR A → G polymorphism have been studied by using PCR-RFLP method. It was found that the NF-κB1 -94ins/delATTG DD genotype and D allele frequencies were higher in patients than healthy controls and the presence of the DD genotype has a 3.5-fold increased risk of the disease (P: 0.014). This study is the first to investigate the NF-κB1 -94ins/delATTG and NF-κBIA 3′UTR A → G polymorphism together in the Turkish population. According to the results, the NF-κB1 -94ins/del ATTG promoter polymorphism may have a role in lung carcinogenesis and prognosis.
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Hayashi R, Tahara T, Yamaaki T, Saito T, Matsunaga K, Hayashi N, Fukumura A, Ozaki K, Nakamura M, Shiroeda H, Tsutsumi M, Shibata T, Arisawa T. -449 C>G polymorphism of NFKB1 gene, coding nuclear factor-kappa-B, is associated with the susceptibility to ulcerative colitis. World J Gastroenterol 2012; 18:6981-6. [PMID: 23322997 PMCID: PMC3531683 DOI: 10.3748/wjg.v18.i47.6981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/26/2012] [Accepted: 08/15/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the association between a polymorphism -449 C>G (rs72696119) in 5’-UTR of NFKB1 with ulcerative colitis (UC).
METHODS: The studied population comprised 639 subjects, including patients with UC (UC cases, n = 174) and subjects without UC (controls, n = 465). We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism.
RESULTS: The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%, respectively (P = 0.10). Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls (P = 0.017), and the GG homozygote was significantly associated with susceptibility to UC [odds ratio (OR), 1.88; 95%CI, 1.13-3.14]. In male subjects, the GG homozygote was associated with an increased risk for UC (OR, 3.10; 95%CI, 1.47-6.54; P = 0.0053), whereas this association was not found in female subjects. In addition, the GG homozygote was significantly associated with the risk of non-continuous disease (OR, 2.06; 95%CI, 1.12-3.79; P = 0.029), not having total colitis (OR, 2.40; 95%CI, 1.09-3.80, P = 0.040), disease which developed before 20 years of age (OR, 2.80; 95%CI, 1.07-7.32, P = 0.041), no hospitalization (OR, 2.28; 95%CI, 1.29-4.05; P = 0.0090) and with a maximum of 8 or less on the UCDAI score (OR, 2.45; 95%CI, 1.23-4.93; P = 0.022).
CONCLUSION: Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC. This polymorphism influences the susceptibility to and pathophysiological features of UC.
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Vu D, Tellez-Corrales E, Sakharkar P, Kissen MS, Shah T, Hutchinson I, Min DI. Impact of NF-κB gene polymorphism on allograft outcome in Hispanic renal transplant recipients. Transpl Immunol 2012; 28:18-23. [PMID: 23153769 DOI: 10.1016/j.trim.2012.11.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 10/29/2012] [Accepted: 11/02/2012] [Indexed: 11/24/2022]
Abstract
BACKGROUND The dimeric NF-κB transcription factors play critical roles in diverse cellular processes including adaptive and innate immunity, cell differentiation, proliferation and apoptosis. It regulates the expression of numerous genes that play a key role in the inflammatory response during kidney allograft rejection. This study aims to determine the association of NF-κB gene polymorphisms with allograft outcomes in the Hispanic renal transplant recipients. METHODS A total of 607 Hispanic renal transplant recipients at St. Vincent Medical Center between 2001 and 2010 were included in this study. The NF-κB genotypes were studied along with clinical data. In the case of NF-κB genotypes, the following single nucleotide polymorphisms (SNPs) were included: NF-κB1 (rs3774959, rs3774932, rs3774937, rs230526, rs230519), NF-κB2 (rs1056890, rs7897947, rs12769316) and NF-κB inducing kinase (NIK) (rs9908330, rs7222094). The association of each genotype with renal allograft survival and acute rejection was evaluated. RESULTS NF-κB1 (rs3774937) CC genotype showed protective association with allograft rejection (OR=0.66, 95% CI=0.44-0.99, p=0.04). There was a significant increase in allograft survival time associated with the NF-κB1 (rs3774959) A allele (OR=0.76, 95% CI=0.60-0.98, p=0.03) while GG genotype was associated with a higher risk of graft failure (OR=1.51, 95% CI=1.02-2.21, p=0.03). There were no associations between polymorphic markers in NF-κB2 and NIK genes with allograft survival or acute rejection. Among non-genetic factors, we found that the use of tacrolimus, a deceased donor, delayed graft function and acute rejection were associated with allograft failure. CONCLUSION The result of present study suggests that NF-κB1 gene polymorphisms may determine the incidence of acute rejection or graft survival among Hispanic allograft recipients.
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Affiliation(s)
- Don Vu
- Mendez National Institute of Transplantation, 2200W 3rd ST, Suite 370, Los Angeles, CA 90057, United States
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Liang M, Xu X, Gong Y, Tang Y, Lin L. Risk association between the NF-κB1 -94ins/delATTG promoter polymorphism and inflammatory bowel diseases: a meta-analysis. Dig Dis Sci 2012; 57:2304-9. [PMID: 22828805 DOI: 10.1007/s10620-012-2164-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 04/03/2012] [Indexed: 01/30/2023]
Abstract
BACKGROUND Extensive investigation of the NF-κB1 -94ins/delATTG promoter polymorphism for risk association with ulcerative colitis (UC) and Crohn's disease (CD) risk has yielded conflicting results. AIMS The objective of this meta-analysis was to evaluate the risk association between the NF-κB1 -94ins/delATTG promoter polymorphism and UC and CD. METHODS All eligible case-control studies of the association of NF-κB1 -94ins/delATTG promoter polymorphism with UC and CD were identified in the Pubmed and Embase databases. From these data, odds ratios (OR) with 95 % confidence intervals (CI) were calculated. Meta-analysis was performed for alleles (D vs. W) and genotypes (DD + WD vs. WW, DD vs. WW + WD, DD vs. WW, WD vs. WW) in a fixed/random effects model. RESULTS Nine case-control studies that included 4,447 cases (2,631 UC and 1,816 CD) and 2,195 controls were identified. Results indicated increased risk association of D allele carriers with UC (D vs. W: OR = 1.08, 95 % CI = 1.01-1.17, P = 0.03; DD vs. WW + WD: OR = 1.16, 95 % CI = 1.01-1.32, P = 0.04 and DD vs. WW: OR = 1.20, 95 % CI = 1.03-1.39, P = 0.02). No risk association was identified with CD. CONCLUSION This meta-analysis indicated that the NF-κB1 -94ins/delATTG promoter polymorphism is a risk factor for UC but not CD.
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Affiliation(s)
- Meilan Liang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Yu Y, Liu H, Jin M, Zhang M, Pan Y, Zhang S, Li Q, Chen K. The joint association of REST and NFKB1 polymorphisms on the risk of colorectal cancer. Ann Hum Genet 2012; 76:269-76. [PMID: 22530801 DOI: 10.1111/j.1469-1809.2012.00709.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Due to the high morbidity and mortality of colorectal cancer (CRC), this study aims to determine the joint association of RE-1-silencing transcription factor (REST) and nuclear factor-κB 1 (NFKB1) genes with CRC in a population-based study. A well-matched case-control study including 390 controls and 388 patients with CRC was enrolled in China. The selected single nucleotide polymorphisms (SNPs) in the REST and NFKB1 genes were genotyped by Illumina SnapShot Chip. After adjustment for important covariates, the associations of SNPs and joint association of REST and NFKB1 with CRC were evaluated by multiple logistic regression models. The subjects with the rs2228991 AA genotype of the REST gene had a decreased risk for CRC (OR = 0.38; 95%CI: 0.19-0.74), compared with the GG genotype. There were no significant associations between three SNPs in the NFKB1 gene, their haplotype and CRC risk. However, a significant combined effect of rs3774959 and rs3774964 in the NFKB1 gene with rs2228991 in the REST gene on CRC risk was observed. In conclusion, the present study found that mutation in the REST gene rather than the NFKB1 gene was associated with the risk of CRC. Furthermore, significant REST-NFKB1 joint association was observed for CRC, colon cancer and rectal cancer risk.
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Affiliation(s)
- Yunxian Yu
- Department of Epidemiology & Health Statistics, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China
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Gao M, Wang CH, Sima X, Han XM. NFKB1−94 Insertion/Deletion ATTG Polymorphism Contributes to Risk of Systemic Lupus Erythematosus. DNA Cell Biol 2012; 31:611-5. [PMID: 22013908 DOI: 10.1089/dna.2011.1389] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Ming Gao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Chun-Hui Wang
- Department of Neurosurgery, Jilin Province Hospital, Changchun, Jilin, People's Republic of China
| | - Xiutian Sima
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xue-Mei Han
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People's Republic of China
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Andersen V, Christensen J, Ernst A, Jacobsen BA, Tjønneland A, Krarup HB, Vogel U. Polymorphisms in NF-κB, PXR, LXR, PPARγ and risk of inflammatory bowel disease. World J Gastroenterol 2011; 17:197-206. [PMID: 21245992 PMCID: PMC3020373 DOI: 10.3748/wjg.v17.i2.197] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Revised: 08/14/2010] [Accepted: 08/21/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease (IBD).
METHODS: Genotypes of nuclear factor (NF)-κB (NFKB1) NFκB -94ins/del (rs28362491); peroxisome proliferator-activated receptor (PPAR)-γ (PPARγ) PPARγ Pro12Ala (rs 1801282) and C1431T (rs 3856806); pregnane X receptor (PXR) (NR1I2) PXR A-24381C (rs1523127), C8055T (2276707), and A7635G (rs 6785049); and liver X receptor (LXR) (NR1H2) LXR T-rs1405655-C and T-rs2695121-C were assessed in a Danish case-control study of 327 Crohn’s disease patients, 495 ulcerative colitis (UC) patients, and 779 healthy controls. Odds ratio (OR) and 95% CI were estimated by logistic regression models.
RESULTS: The PXR A7635G variant, the PPARγ Pro12Ala and LXR T-rs2695121-C homozygous variant genotypes were associated with risk of UC (OR: 1.31, 95% CI: 1.03-1.66, P = 0.03, OR: 2.30, 95% CI: 1.04-5.08, P = 0.04, and OR: 1.41, 95% CI: 1.00-1.98, P = 0.05, respectively) compared to the corresponding homozygous wild-type genotypes. Among never smokers, PXR A7635G and the LXR T-rs1405655-C and T-rs2695121-C variant genotypes were associated with risk of IBD (OR: 1.41, 95% CI: 1.05-1.91, P = 0.02, OR: 1.63, 95% CI: 1.21-2.20, P = 0.001, and OR: 2.02, 95% CI: 1.36-2.99, P = 0.0005, respectively) compared to the respective homozygous variant genotypes. PXR A7635G (rs6785049) variant genotype was associated with a higher risk of UC diagnosis before the age of 40 years and with a higher risk of extensive disease (OR: 1.34, 95% CI: 1.03-1.75 and OR: 2.49, 95% CI: 1.24-5.03, respectively).
CONCLUSION: Common PXR and LXR polymorphisms may contribute to risk of IBD, especially among never smokers.
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Fan Y, Yu W, Ye P, Wang H, Wang Z, Meng Q, Duan Y, Liang X, An W. NFKB1 insertion/deletion promoter polymorphism increases the risk of advanced ovarian cancer in a Chinese population. DNA Cell Biol 2010; 30:241-5. [PMID: 21138333 DOI: 10.1089/dna.2010.1107] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Ovarian cancer is the leading cause of death among all gynecological cancers. This is mainly attributed to its frequent presentation at an advanced stage (International Federation of Gynecology and Obstetrics stage III-IV). Nuclear factor-kappaB (NF-κB) is critically involved in the carcinogenesis and development of ovarian cancer. A functional insertion/deletion polymorphism (-94 ins/del ATTG) in the promoter region of the NFKB1 gene, which encodes the p50 subunit of the NF-κB protein, has been recently identified and shown to increase the susceptibility to many diseases. The purpose of this study was to explore the association between this polymorphism and the risk of advanced ovarian cancer in a Chinese population. A total of 179 advanced ovarian cancer patients and 223 healthy controls were recruited into this study. Genotypes were determined using polymerase chain reaction-capillary electrophoresis method. The insertion increased the risk of advanced ovarian cancer (odds ratio = 2.111, 95% confidence intervals = 1.125-3.961, p = 0.019 for heterozygote insertion, and odds ratio = 2.656, 95% confidence intervals = 1.397-5.051, p = 0.002 for homozygote insertion) compared with homozygote deletion. Similar results were seen in age-adjusted analyses (p < 0.05). Our preliminary results suggest that NFKB1-94 ins/del ATTG promoter polymorphism may be associated with increased susceptibility to advanced ovarian cancer.
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Affiliation(s)
- Yaxin Fan
- Dalian Blood Center, Dalian Institute of Blood Transfusion, Dalian, China.
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Zou YF, Wang F, Feng XL, Tao JH, Zhu JM, Pan FM, Su H. Association of NFKB1 -94ins/delATTG promoter polymorphism with susceptibility to autoimmune and inflammatory diseases: a meta-analysis. ACTA ACUST UNITED AC 2010; 77:9-17. [DOI: 10.1111/j.1399-0039.2010.01559.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Zhou B, Rao L, Peng Y, Wang Y, Qie M, Zhang Z, Song Y, Zhang L. A Functional Promoter Polymorphism inNFKB1Increases Susceptibility to Endometriosis. DNA Cell Biol 2010; 29:235-9. [PMID: 20218898 DOI: 10.1089/dna.2009.0992] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Bin Zhou
- Laboratory of Molecular Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Li Rao
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Ying Peng
- Department of Cardiology, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Yanyun Wang
- Department of Immunology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China
| | - Mingrong Qie
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Zhu Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Yaping Song
- Laboratory of Molecular Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Lin Zhang
- Laboratory of Molecular Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
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Wang JF, Bian JJ, Wan XJ, Zhu KM, Sun ZZ, Lu AD. NFKB1-94ins/del polymorphism is not associated with lung injury after cardiopulmonary bypass. Anaesthesia 2009; 65:158-62. [PMID: 19995347 DOI: 10.1111/j.1365-2044.2009.06186.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Nuclear factor (NF)-kappaB (NFKB1)-94ins/del is an important polymorphism that affects promoter activity of the NFKB1 gene and is potentially associated with several inflammatory diseases. We investigated the association of this polymorphism with lung injury after cardiac surgery and cardiopulmonary bypass in a prospective cohort study of 283 patients. Genotyping was performed by high resolution melting analysis; analysis indicated no association of NFKB1 with postoperative lung injury (p = 0.064). Relative risks of the del allele and the del/del genotype were 1.34 (95% CI 1.02-1.75) and 1.74 (95% CI 1.00-3.05) respectively. Logistic regression analysis (with factors including age, peripheral vascular disease and surgical duration as risk factors of lung injury after cardiac surgery with cardiopulmonary bypass) also failed to confirm that the NFKB1 genotype is influential for lung injury (p = 0.113). We conclude that, contrary to some other evidence, the NFKB1-94ins/del polymorphism is not associated with lung injury after cardiac surgery with cardiopulmonary bypass.
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Affiliation(s)
- J F Wang
- Department of Anesthesiology and Intensive Care Unit, Changhai Hospital, Second Military Medical University, Shanghai, China
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16
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Zhou B, Qie M, Wang Y, Yan L, Zhang Z, Liang A, Wang T, Wang X, Song Y, Zhang L. Relationship between NFKB1 -94 insertion/deletion ATTG polymorphism and susceptibility of cervical squamous cell carcinoma risk. Ann Oncol 2009; 21:506-511. [PMID: 19892748 DOI: 10.1093/annonc/mdp507] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND A very high expression of nuclear factor-kappa B protein (nuclear p50, encoded by NFKB1) in high-grade squamous intraepithelial lesion and invasive cancers has been observed. The aim of this study was to determine whether the functional NFKB1 -94 insertion/deletion ATTG polymorphism (rs28362491) is associated with cervical squamous cell carcinoma (CSCC). MATERIALS AND METHODS PCR-polyacrylamide gel electrophoresis method was used to genotype the NFKB1 -94 insertion/deletion ATTG polymorphism in 233 women with CSCC and 365 ethnicity-matched healthy control women. The genotyping method was confirmed by the DNA sequencing analysis. RESULTS The frequency of ATTG(2)/ATTG(2) genotype and ATTG(2) allele in the CSCC patients was significantly higher than that of controls, indicating that the -94 insertion/deletion ATTG polymorphism in NFKB1 promoter was associated with CSCC [P = 0.001, odds ratio (OR) = 2.560, 95% confidence interval (CI) 1.459-4.492 and P = 0.001, OR = 1.493, 95% CI 1.168-1.908, respectively]. Results of stratified analyses revealed that this polymorphism is associated with younger age (< or =35 years) and positive parametrial invasion but not with tumor differentiation, high clinical stage or lymph node status. CONCLUSION Our results indicate that the functional NFKB1 -94 insertion/deletion ATTG polymorphism is associated with CSCC, especially with younger age (< or =35 years) and positive parametrial invasion of CSCC patients.
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Affiliation(s)
- B Zhou
- Laboratory of Molecular Translational Medicine
| | - M Qie
- Department of Obstetrics and Gynecology, West China Second University Hospital
| | - Y Wang
- Department of Immunology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, People's Republic of China
| | - L Yan
- Department of Obstetrics and Gynecology, West China Second University Hospital
| | - Z Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital
| | - A Liang
- Department of Obstetrics and Gynecology, West China Second University Hospital
| | - T Wang
- Laboratory of Molecular Translational Medicine
| | - X Wang
- Laboratory of Molecular Translational Medicine
| | - Y Song
- Laboratory of Molecular Translational Medicine
| | - L Zhang
- Laboratory of Molecular Translational Medicine.
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17
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Marcos M, Pastor I, González-Sarmiento R, Laso FJ. A functional polymorphism of the NFKB1 gene increases the risk for alcoholic liver cirrhosis in patients with alcohol dependence. Alcohol Clin Exp Res 2009; 33:1857-62. [PMID: 19673747 DOI: 10.1111/j.1530-0277.2009.01023.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND The genetic basis for the predisposition to alcoholic liver cirrhosis (ALC) remains unknown. Increasing evidence supports a role for the nuclear factor (NF)-kappaB, the NF-kappaB inhibitor alpha (NFKBIA), and the peroxisome proliferator-activated receptor (PPAR)-gamma in the pathogenesis of alcoholic liver disease, raising the possibility that common polymorphisms in genes encoding these molecules may confer susceptibility to ALC. The objective of this study was to analyze the relationship between common polymorphisms in NFKB1, NFKBIA, and PPARG2 genes and the presence of ALC. METHODS A total of 258 male alcoholics (161 without liver disease and 97 with ALC) and 101 healthy controls were genotyped for the -94ins/delATTG NFKB1, 3'-UTR+126G>A NFKBIA, and 34C>G PPARG2 polymorphisms. The association of these genetic variants with ALC was tested in alcoholic patients with alcohol abuse and alcohol dependence. A logistic regression analysis was further performed to analyze the model of inheritance. RESULTS We found an association between the presence of the deletion allele in NFKB1 polymorphism and ALC in patients with alcohol dependence. We found no association between NFKBIA and PPARG2 polymorphisms and the presence of ALC. CONCLUSIONS The deletion allele of the -94ins/del NFKB1 polymorphism could be associated with a higher risk of developing ALC through an increase in inflammation, as supported by previous data.
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Affiliation(s)
- Miguel Marcos
- The Unidad de Alcoholismo, Servicio de Medicina Interna II, Hospital Universitario de Salamanca, Spain
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18
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Kim JG, Sohn SK, Chae YS, Moon JH, Kim SN, Kang BW, Kim GC, Lee MH, Jeon SW, Chung HY, Yu W. No Association of the NFKB1 Insertion/Deletion Promoter Polymorphism with Survival in Patients with Gastric Cancer. Jpn J Clin Oncol 2009; 39:497-501. [DOI: 10.1093/jjco/hyp056] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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19
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Zhou B, Rao L, Peng Y, Wang Y, Li Y, Gao L, Chen Y, Xue H, Song Y, Liao M, Zhang L. Functional polymorphism of the NFKB1 gene promoter is related to the risk of dilated cardiomyopathy. BMC MEDICAL GENETICS 2009; 10:47. [PMID: 19480714 PMCID: PMC2692851 DOI: 10.1186/1471-2350-10-47] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 05/31/2009] [Indexed: 11/23/2022]
Abstract
Background Previous studies in experimental and human heart failure showed that nuclear factor kappa B (NF-κB) is chronically activated in cardiac myocytes, suggesting an important involvement of NF-κB in the cardiac remodeling process. A common insertion/deletion (-94 insertion/deletion ATTG, rs28362491) located between two putative key promoter regulatory elements in the NFKB1 gene was identified which seems to be the first potential functional NFKB1 genetic variation. The main goal of the present investigation was to investigate the NFKB1 -94 insertion/deletion ATTG polymorphism in relation to risk of dilated cardiomyopathy (DCM). Methods A total of 177 DCM patients and 203 control subjects were successfully investigated. The NFKB1 -94 insertion/deletion ATTG polymorphism was genotyped by using PCR-PAGE. Results Genotype frequency of NFKB1 -94 insertion/deletion ATTG polymorphism in DCM patients was significantly different from that in control subjects (P = 0.015) and the ATTG2 carrier (ATTG1/ATTG2 + ATTG2/ATTG2) was susceptible to DCM. Conclusion Our data suggested that NFKB1 -94 insertion/deletion ATTG polymorphism is associated with DCM.
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Affiliation(s)
- Bin Zhou
- Laboratory of Molecular Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, PR China.
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20
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Szamosi T, Lakatos PL, Szilvasi A, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Szabo O, Satori A, Tulassay Z, Miheller P, Horvath HC, Papp J, Tordai A, Andrikovics H. The 3'UTR NFKBIA variant is associated with extensive colitis in Hungarian IBD patients. Dig Dis Sci 2009; 54:351-359. [PMID: 18716880 DOI: 10.1007/s10620-008-0351-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Accepted: 05/15/2008] [Indexed: 12/09/2022]
Abstract
PURPOSE In previous studies the NFKBIA 3'UTR (untranslated region) AA genotype was associated with Crohn's disease (CD), while the NFKB1-94ins/delATTG mutation increased the risk for ulcerative colitis (UC). The aim of our study was to investigate these two polymorphisms and patients' response to medical therapy and/or disease phenotype in Hungarian inflammatory bowel disease (IBD) patients. METHODS NFKBIA 3'UTR- and NFKB1-94ins/delATTG polymorphisms were investigated in 415 unrelated IBD patients (CD: 266 patients, mean age 35.2 +/- 12.1 years, duration 8.7 +/- 7.5 years; UC patients: 149, mean age 44.4 +/- 15.4 years, duration 10.7 +/- 8.9 years) and 149 controls by PCR-restriction fragment length polymorphism (RFLP) analysis. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS The NFKBIA 3'UTR and NFKB1-94ins/delATTG genotypes and allele frequencies were not significantly different among IBD and controls. In patients with UC, the 3'UTR GG genotype was associated with extensive colitis (55.3 vs. 29.4%, odds ratio 2.97, 95% confidence interval 1.45-6.08). The presence of variant alleles did not predict response to steroids, infliximab, or need for surgery. CONCLUSIONS The NFKBIA 3'UTR GG genotype was associated with an increased risk for extensive colitis in Hungarian patients. In contrast, variant alleles did not predict response to medical therapy or need for surgery.
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Affiliation(s)
- Tamas Szamosi
- 1st Department of Medicine, Semmelweis University, Koranyi st. 2/A, 1083, Budapest, Hungary
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21
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Sáenz-López P, Carretero R, Cózar JM, Romero JM, Canton J, Vilchez JR, Tallada M, Garrido F, Ruiz-Cabello F. Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer. BMC Cancer 2008; 8:382. [PMID: 19099590 PMCID: PMC2626602 DOI: 10.1186/1471-2407-8-382] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Accepted: 12/19/2008] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Inflammation has been implicated as an etiological factor in several human cancers, including prostate cancer. Allelic variants of the genes involved in inflammatory pathways are logical candidates as genetic determinants of prostate cancer risk. The purpose of this study was to investigate whether single nucleotide polymorphisms of genes that lead to increased levels of pro-inflammatory cytokines and chemokines are associated with an increased prostate cancer risk. METHODS A case-control study design was used to test the association between prostate cancer risk and the polymorphisms TNF-A-308 A/G (rs 1800629), RANTES-403 G/A (rs 2107538), IL1-A-889 C/T (rs 1800587) and MCP-1 2518 G/A (rs 1024611) in 296 patients diagnosed with prostate cancer and in 311 healthy controls from the same area. RESULTS Diagnosis of prostate cancer was significantly associated with TNF-A GA + AA genotype (OR, 1.61; 95% CI, 1.09-2.64) and RANTES GA + AA genotype (OR, 1.44; 95% CI, 1.09-2.38). A alleles in TNF-A and RANTES influenced prostate cancer susceptibility and acted independently of each other in these subjects. No epistatic effect was found for the combination of different polymorphisms studied. Finally, no overall association was found between prostate cancer risk and IL1-A or MCP-1 polymorphisms. CONCLUSION Our results and previously published findings on genes associated with innate immunity support the hypothesis that polymorphisms in proinflammatory genes may be important in prostate cancer development.
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Affiliation(s)
- Pablo Sáenz-López
- Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Rafael Carretero
- Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - José Manuel Cózar
- Servicio de Urología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - José Maria Romero
- Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Julia Canton
- Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - José Ramón Vilchez
- Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Miguel Tallada
- Servicio de Urología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | | | - Francisco Ruiz-Cabello
- Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
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22
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A functional insertion/deletion polymorphism in the promoter region of NFKB1 gene increases susceptibility for nasopharyngeal carcinoma. Cancer Lett 2008; 275:72-6. [PMID: 19006646 DOI: 10.1016/j.canlet.2008.10.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2008] [Revised: 09/17/2008] [Accepted: 10/02/2008] [Indexed: 12/11/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. Nuclear factor-kappaB (NF-kappaB)-activation plays critical roles in Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) mediated tumorigenesis in NPC. A functional insertion/deletion polymorphism (-94 insertion/deletion ATTG) in the promoter of NFKB1 gene, which encodes the p50 subunit of NF-kappaB protein complex, was recently identified. This study found that the frequency of ATTG(2) allele in NPC patients was significantly higher than that in control subjects (66% vs. 57.1%, p=0.015, OR=1.453), suggesting that the functional NFKB1 promoter polymorphism is associated with increased risk for NPC.
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23
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Wu F, Xia Z, Qu Y, Tang Y, Cao D, Sun P, Christiani DC. Genetic polymorphisms of IL-1A, IL-1B, IL-1RN, NFKB1, FAS, and FASL, and risk of silicosis in a Chinese occupational population. Am J Ind Med 2008; 51:843-51. [PMID: 18666137 DOI: 10.1002/ajim.20616] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To test whether polymorphisms in IL-1, NF-KB, FAS, and FASL genes are associated with risk of silicosis. METHODS A case-control study was conducted with 183 silicosis patients and 111 silica-exposed miners who were frequency-matched by age, dust exposure duration, work location, and type of work. Genotype analysis was performed on genomic DNA, using a PCR-RFLP assay. RESULTS Individuals carrying the NFKB1 ins/del genotype had a decreased risk of silicosis (adjusted OR = 0.57, 95% CI = 0.32-0.998, P = 0.049) compared with subjects carrying the ins/ins genotype and individuals with the FAS-1377AA homozygote had a decreased risk of silicosis compared with those with the -1377GG genotype (adjusted OR = 0.42, 95% CI = 0.19-0.93, P = 0.03). The analysis of haplotypes of polymorphisms in FAS showed that there was a 2.71-fold (OR = 2.71, 95% CI = 1.22-6.03, P = 0.011) increased risk of silicosis for subjects with alleles of FAS-1377G and FAS-670G, compared with those carrying alleles of FAS-1377G and FAS-670A. CONCLUSION Although the polymorphisms at NFKB1, FAS-1377, and extended haplotype FAS-1377G/-670G may play a role in the development of silicosis in the Chinese population, our findings should be verified by larger studies with >1 case/control ratio.
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Affiliation(s)
- Fen Wu
- Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai, China
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24
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Li H, Gao L, Shen Z, Li CY, Li K, Li M, Lv YJ, Li CX, Gao TW, Liu YF. Association study of NFKB1 and SUMO4 polymorphisms in Chinese patients with psoriasis vulgaris. Arch Dermatol Res 2008; 300:425-33. [DOI: 10.1007/s00403-008-0843-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Revised: 02/05/2008] [Accepted: 02/26/2008] [Indexed: 01/28/2023]
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Abstract
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.
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26
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Lewander A, Butchi AKR, Gao J, He LJ, Lindblom A, Arbman G, Carstensen J, Zhang ZY, Sun XF. Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations. Scand J Gastroenterol 2007; 42:1332-8. [PMID: 17852842 DOI: 10.1080/00365520701396026] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE An insertion/deletion polymorphism (-94ins/delATTG) in the promoter region of the NFKB1 gene correlates to an increased risk of ulcerative colitis, a known risk factor for colorectal cancer, but this polymorphism has not been studied in colorectal cancer patients. The purpose of this study was to investigate whether this polymorphism is related to colorectal cancer risk and clinicopathological variables. MATERIAL AND METHODS Case samples were taken from four groups of Swedish patients: 193 unselected patients, 90 patients with > or =3 affected 1st-degree relatives, 85 patients with 2 affected 1st-degree relatives, and 109 sporadic cancer patients, and one group of 193 unselected Chinese patients. Controls included 439 Swedish and 458 Chinese healthy individuals. Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. RESULTS The deletion increased the risk of colorectal cancer among Swedish unselected patients (OR =3.81, 95% CI: 2.17-6.69, p <0.0001 for heterozygote deletion, and OR=4.65, 95% CI: 2.43-8.89, p <0.0001 for homozygote deletion) and sporadic cancer patients (OR =7.73, 95% CI: 3.06-19.57, p <0.0001 for heterozygote deletion, and OR =6.58, 95% CI: 2.35-18.43, p <0.0001 for homozygote deletion) compared to homozygote insertion (wild-type), but not among the other Swedish or Chinese patients (p >0.05). Similar evidence was seen in age-adjusted analyses (p <0.0001). The polymorphism did not correlate to clinicopathological variables (p >0.05). CONCLUSIONS Deletion of the polymorphism was associated with increased susceptibility to sporadic colorectal cancers in the Swedish population, but not in the Swedish patients with a family history of colorectal cancer or in Chinese patients.
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Affiliation(s)
- Andreas Lewander
- Department of Oncology, Institute of Biomedicine and Surgery, University of Linköping, Linköping, Sweden
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Latiano A, Palmieri O, Valvano MR, Bossa F, Latiano T, Corritore G, DeSanto E, Andriulli A, Annese V. Evaluating the role of the genetic variations of PTPN22, NFKB1, and FcGRIIIA genes in inflammatory bowel disease: a meta-analysis. Inflamm Bowel Dis 2007; 13:1212-1219. [PMID: 17600378 DOI: 10.1002/ibd.20185] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND We tested several polymorphisms of genes involved in the mucosal immune system in a population of inflammatory bowel disease (IBD) patients to investigate their possible implication in disease predisposition. METHODS Polymorphisms of 3 candidate genes (PTPN22, NFkB1, and FcGRIIIA) were investigated in 649 IBD patients (343 with Crohn's disease [CD] and 306 with ulcerative colitis [UC]), 176 unaffected relatives, and 256 healthy controls. Allele and genotype frequencies were correlated with clinical characteristics and major variants of the CARD15 gene. Our findings were pooled in a meta-analysis with the available studies in the literature. RESULTS No significant difference for the PTPN22 and NFkB1 variants was found. In contrast, allele and genotype frequencies of the G559T allele of the FcGRIIIA gene were significantly different in CD patients compared to controls (allele T 12% versus 8%, odds ratio [OR] = 1.58, 95% confidence interval [CI] 1.06-2.35; GT genotype 23% versus 16%, OR = 1.64, 95% CI = 1.08-2.5). However, no significant overtransmission of the T allele was confirmed at the family-based analysis. For all genes, neither an interaction with CARD15 gene, nor a significant difference at genotype/phenotype analysis was demonstrated, included response to medical therapy. CONCLUSIONS Although involved in autoimmune diseases, the PTPN22 and NFkB1 genes do not seem involved in the IBD predisposition, also according to meta-analysis results. The association with the G559T polymorphism of the FcGRIIIA gene in CD patients deserves further investigation.
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Affiliation(s)
- Anna Latiano
- Unità Operativa di Gastroenterologia e Laboratorio di Ricerca Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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28
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Kurylowicz A, Hiromatsu Y, Jurecka-Lubieniecka B, Kula D, Kowalska M, Ichimura M, Koga H, Kaku H, Bar-Andziak E, Nauman J, Jarzab B, Ploski R, Bednarczuk T. Association of NFKB1 -94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease. Genes Immun 2007; 8:532-8. [PMID: 17690684 DOI: 10.1038/sj.gene.6364418] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Recently, a functional polymorphism in the NFKB1 gene promoter (-94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish-Gliwice and Japanese-Kurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the -94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P=0.00005; OR=1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P=0.009; OR=1.49 (1.10-2.01)), and the age of disease onset (P=0.009; OR=1.45 (1.09-1.91)). Our results suggest that NFKB1 -94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD.
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Affiliation(s)
- A Kurylowicz
- Department of Endocrinology, Medical Research Center, Polish Academy of Science, Warsaw, Poland
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De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun 2007; 8:387-97. [PMID: 17538633 DOI: 10.1038/sj.gene.6364398] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.
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Affiliation(s)
- P L De Jager
- Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
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30
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Riemann K, Becker L, Struwe H, Nückel H, Dührsen U, Alakus H, Winde G, Neuhäuser M, Rübben H, Schmitz KJ, Wohlschlaeger J, Schmid KW, Siffert W. No association of the NFKB1 insertion/deletion promoter polymorphism with survival in colorectal and renal cell carcinoma as well as disease progression in B-cell chronic lymphocytic leukemia. Pharmacogenet Genomics 2007; 16:783-8. [PMID: 17047486 DOI: 10.1097/01.fpc.0000230414.74726.f6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor that plays a major role in the regulation of genes involved in immune and inflammatory response. Activation of NF-kappaB has also been associated with apoptosis and proliferation, thereby potentially also controlling oncogenesis. A functional insertion/deletion polymorphism has been identified in the promoter region of NFKB1, which apparently controls the transcription of NF-kappaB. The purpose of this study was, therefore, to investigate associations of the -94ins/delATTG polymorphism with susceptibility and survival of patients with different types of cancer. EXPERIMENTAL DESIGN Genotype distributions in patients with colorectal carcinoma (n=139), B-cell chronic lymphocytic leukemia (n=72) and clear cell renal cell carcinoma (n=140), and in controls (n=307) were analyzed by pyrosequencing and compared with each other as well as associated with clinico-pathological parameters and demographic data. RESULTS No statistically significant differences in both allele and genotype frequencies were observed between patients and healthy controls. Likewise, no association between -94ins/delATTG alleles and survival or disease progression was noticed. CONCLUSION These results suggest that the NFKB1 promoter polymorphism has no effect on risk and course of disease in the three cancer entities that were analyzed.
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MESH Headings
- Aged
- Carcinoma/genetics
- Carcinoma/mortality
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/mortality
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/mortality
- Disease Progression
- Female
- Genetic Predisposition to Disease
- Genotype
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/mortality
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/mortality
- Male
- Middle Aged
- Mutagenesis, Insertional
- NF-kappa B p50 Subunit/genetics
- Polymorphism, Genetic
- Promoter Regions, Genetic
- Sequence Deletion
- Survival Analysis
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Affiliation(s)
- Kathrin Riemann
- Institute of Pharmacogenetics, University Hospital Essen, Essen, Germany.
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Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 2007; 39:177-99. [PMID: 17457716 DOI: 10.1080/07853890701197615] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
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Affiliation(s)
- Philippe Goyette
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
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Glas J, Török HP, Tonenchi L, Müller-Myhsok B, Mussack T, Wetzke M, Klein W, Epplen JT, Griga T, Schiemann U, Lohse P, Seiderer J, Schnitzler F, Brand S, Ochsenkühn T, Folwaczny M, Folwaczny C. Role of the NFKB1 -94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes. Inflamm Bowel Dis 2006; 12:606-11. [PMID: 16804398 DOI: 10.1097/01.ibd.0000225346.23765.6b] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Recently, an association of the NFKB1 polymorphism -94ins/delATTG with ulcerative colitis (UC) has been reported. This 4-bp insertion/deletion polymorphism is localized in the promoter region of the NFKB1 gene and appears to be functionally relevant. The aim of the present study was to confirm the association of the -94ins/delATTG (W/D) NFKB1 promoter polymorphism with UC in a population of German origin and to test for a potential association with Crohn's disease (CD). Furthermore, potential interactions of the -94ins/delATTG polymorphism with the IKBL and the IL-1RN genes should be determined. MATERIALS AND METHODS The study population comprised 630 patients with CD, 365 patients with UC, and 974 healthy controls. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism analysis. For statistical evaluation, the chi-square test and the Fisher exact test were used. RESULTS No significant association of the W/D NFKB1 polymorphism with CD or UC was detected. In addition, no significant interactions between the -94ins/delATTG NFKB1 polymorphism and polymorphisms within the IKBL and the IL-1RN genes, respectively, were found in CD or UC. Also, no significant interactions of the NFKB1 polymorphism with mutations of the CARD15/NOD2 gene and with clinical phenotypes were detected in CD. Moreover, no associations of the NFKB1 polymorphism were found in UC depending on disease localization. CONCLUSIONS The present study could not confirm the reported association of the -94ins/delATTG NFKB1 polymorphism with UC and also found no evidence for a role of this polymorphism in CD. The results do not give evidence for a role of this NFKB1 polymorphism in the pathogenesis of UC and CD.
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Affiliation(s)
- Jürgen Glas
- Chirurgische Klinik und Poliklinik-Innenstadt, München, Germany.
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Rueda B, Núñez C, López-Nevot MA, Paz Ruiz M, Urcelay E, De la Concha EG, Martín J. Functional polymorphism of the NFKB1 gene promoter is not relevant in predisposition to celiac disease. Scand J Gastroenterol 2006; 41:420-3. [PMID: 16635909 DOI: 10.1080/00365520500325929] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The nuclear factor (NF)-kappaB is one of the pivotal regulators of autoimmunity and inflammation, which has been shown to be activated in the inflamed mucosa of patients with celiac disease (CD). Recently, in the NFKB1 gene promoter region, a common insertion/deletion (-94ins/delATTG) polymorphism located between two putative key promoter regulatory elements was described. The aim of this study was to investigate the contribution of the -94ins/delATTG NFKB1 gene promoter functional variant to CD genetic predisposition. MATERIAL AND METHODS A case-control cohort comprising 478 patients with CD and 711 healthy controls as well as a panel of 196 celiac families was genotyped for the 94ins/delATTG NFKB1 polymorphism, using a polymerase chain reaction (PCR) method combined with fluorescence technology. RESULTS We found no statistically significant differences between CD patients and controls when the -94ins/delATTG genotype and allele distributions were compared. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of -94ins/delATTG alleles to the affected offspring. CONCLUSIONS From these results, it could be suggested that the -94ins/delATTG NFKB1 polymorphism does not play a major role in CD susceptibility.
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Affiliation(s)
- Blanca Rueda
- Instituto de Parasitología y Biomedicina López Neyra, Granada, Spain
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Borm MEA, van Bodegraven AA, Mulder CJJ, Kraal G, Bouma G. A NFKB1 promoter polymorphism is involved in susceptibility to ulcerative colitis. Int J Immunogenet 2006; 32:401-5. [PMID: 16313306 DOI: 10.1111/j.1744-313x.2005.00546.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nuclear factor kappaB (NF-kappaB) designates a group of critical transcription factors involved in a variety of immunologic and/or inflammatory processes. Conceivably, genes involved in the NF-kappaB pathway make interesting candidate genes for chronic inflammatory disorders, including the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC). In two mouse models of colitis, strong linkage has been observed with a locus on chromosome 3 that harbours the Nfkb1 gene. In addition, a polymorphism in the promoter region of the human NFKB1 gene was found to be associated with susceptibility to UC. In this study, we searched to confirm this previously found association in IBD in a different population. Allele and genotype frequencies of the -94 ins/delATTG polymorphism were determined in 266 unrelated Dutch Caucasian IBD patients (127 UC, 139 CD), and 155 matched healthy controls. The allele frequency of the deletion was significantly higher in UC patients (P = 0.019), but not in CD patients, compared to healthy controls, and the UC patients homozygous for the -94 ATTG deletion had a younger age of onset. Our findings confirm the previously found association between this polymorphism and susceptibility to UC in an independent study population and adds further evidence for the role of this gene in disease susceptibility.
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Affiliation(s)
- M E A Borm
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
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