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Marzaban R, Mohamed Samy R, Ahmed Kassem M, Atef M. Multidrug resistance Gene-1 polymorphisms (C3435T and G2677T) and the risk of inflammatory bowel disease in Egyptian patients. Arab J Gastroenterol 2025; 26:3-8. [PMID: 38413324 DOI: 10.1016/j.ajg.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 10/23/2023] [Accepted: 12/30/2023] [Indexed: 02/29/2024]
Abstract
BACKGROUND AND STUDY AIMS The multidrug resistance 1 (MDR1) gene is a gene involved in the pathogenesis of inflammatory bowel disease (IBD).The aim of the study is to investigate the association of MDR-1 gene polymorphisms (C2345T and G2677T) and IBD incidence in Egyptian patients, and its relation with disease severity. PATIENTS AND METHODS This is a case-control study where genotyping of MDR-1 gene C3435T and G2677T single nucleotide polymorphisms (SNPs) were assayed. RESULTS Forty naïve IBD patients, who were composed of 25 UC and 15CD, were compared to 60 healthy controls. They were young aged with significant female predominance, particularly in CD (P = 0.004). UC was mainly (48 %) presented in moderate severity while CD was mainly (53.3 %) presented with mild severity. MDR-1 gene C3435T SNP was not statistically related to IBD, whether in terms of genotypes or alleles, yet its T allele was significantly related to moderate cases of UC (P = 0.014). However, GG genotype of G2677T SNP was significantly low in IBD (P = 0.013), while TT genotype and T allele were significantly related to CD (P = 0.011, and 0.012 respectively). Moreover, G allele proved to be associated significantly with moderate cases of UC (P = 0.001) and mild cases of CD (P = 0.002). CONCLUSIONS MDR-I gene G2677T SNP GG genotype proved to be protective against IBD, thus may be considered in diagnostic workup of IBD including its severity.
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Affiliation(s)
- Raghda Marzaban
- Endemic Medicine Department-Faculty of Medicine-Cairo University, Egypt
| | - Rania Mohamed Samy
- Clinical pathology department-Faculty of Medicine-Cairo University, Egypt
| | - Mona Ahmed Kassem
- Department of Hepatology-Students᾿ hospital-Ministry of Health, Giza, Egypt
| | - Mira Atef
- Endemic Medicine Department-Faculty of Medicine-Cairo University, Egypt.
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2
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Stoeltje L, Luc JK, Haddad T, Schrankel CS. The roles of ABCB1/P-glycoprotein drug transporters in regulating gut microbes and inflammation: insights from animal models, old and new. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230074. [PMID: 38497255 PMCID: PMC10945405 DOI: 10.1098/rstb.2023.0074] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 02/13/2024] [Indexed: 03/19/2024] Open
Abstract
Commensal enteric bacteria have evolved systems that enable growth in the ecologic niche of the host gastrointestinal tract. Animals evolved parallel mechanisms to survive the constant exposure to bacteria and their metabolic by-products. We propose that drug transporters encompass a crucial system to managing the gut microbiome. Drug transporters are present in the apical surface of gut epithelia. They detoxify cells from small molecules and toxins (xenobiotics) in the lumen. Here, we review what is known about commensal structure in the absence of the transporter ABCB1/P-glycoprotein in mammalian models. Knockout or low-activity alleles of ABCB1 lead to dysbiosis, Crohn's disease and ulcerative colitis in mammals. However, the exact function of ABCB1 in these contexts remain unclear. We highlight emerging models-the zebrafish Danio rerio and sea urchin Lytechinus pictus-that are poised to help dissect the fundamental mechanisms of ATP-binding cassette (ABC) transporters in the tolerance of commensal and pathogenic communities in the gut. We and others hypothesize that ABCB1 plays a direct role in exporting inflammatory bacterial products from host epithelia. Interdisciplinary work in this research area will lend novel insight to the transporter-mediated pathways that impact microbiome community structure and accelerate the pathogenesis of inflammatory bowel disease when perturbed. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.
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Affiliation(s)
- Lauren Stoeltje
- Department of Biology, San Diego State University, 5500 Campanile Drive, Life Sciences North, Room 321, San Diego, CA 92182, USA
| | - Jenna K. Luc
- Department of Biology, San Diego State University, 5500 Campanile Drive, Life Sciences North, Room 321, San Diego, CA 92182, USA
| | - Timothaus Haddad
- Department of Biology, San Diego State University, 5500 Campanile Drive, Life Sciences North, Room 321, San Diego, CA 92182, USA
| | - Catherine S. Schrankel
- Department of Biology, San Diego State University, 5500 Campanile Drive, Life Sciences North, Room 321, San Diego, CA 92182, USA
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Korkor MS, El-Desoky T, Mosaad YM, Salah DM, Hammad A. Multidrug resistant 1 (MDR1) C3435T and G2677T gene polymorphism: impact on the risk of acute rejection in pediatric kidney transplant recipients. Ital J Pediatr 2023; 49:57. [PMID: 37198710 DOI: 10.1186/s13052-023-01469-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 05/01/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Tacrolimus is the backbone drug in kidney transplantation. Single nucleotide polymorphism of Multidrug resistant 1 gene can affect tacrolimus metabolism consequently it can affect tacrolimus trough level and incidence of acute rejection. The aim of this study is to investigate the impact of Multidrug resistant 1 gene, C3435T and G2677T Single nucleotide polymorphisms on tacrolimus pharmacokinetics and on the risk of acute rejection in pediatric kidney transplant recipients. METHODS Typing of Multidrug resistant 1 gene, C3435T and G2677T gene polymorphism was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 83 pediatric kidney transplant recipients and 80 matched healthy controls. RESULTS In Multidrug resistant 1 gene (C3435T), CC, CT genotypes and C allele were significantly associated with risk of acute rejection when compared to none acute rejection group (P = 0.008, 0.001 and 0.01 respectively). The required tacrolimus doses to achieve trough level were significantly higher among CC than CT than TT genotypes through the 1st 6 months after kidney transplantation. While, in Multidrug resistant 1 gene (G2677T), GT, TT genotypes and T allele were associated with acute rejection when compared to none acute rejection (P = 0.023, 0.033 and 0.028 respectively). The required tacrolimus doses to achieve trough level were significantly higher among TT than GT than GG genotypes through the 1st 6 months after kidney transplantation. CONCLUSION The C allele, CC and CT genotypes of Multidrug resistant 1 gene (C3435T) and the T allele, GT and TT genotypes of Multidrug resistant 1 gene (G2677T) gene polymorphism may be risk factors for acute rejection and this can be attributed to their effect on tacrolimus pharmacokinetics. Tacrolimus therapy may be tailored according to the recipient genotype for better outcome.
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Affiliation(s)
- Mai S Korkor
- Pediatric Nephrology Unit, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Tarek El-Desoky
- Pediatric respiratory and allergy Unit, Faculty of Medicine, Mansoura University Children's Hospital, Mansoura University, Mansoura, Egypt
| | - Youssef M Mosaad
- Clinical Immunology Unit, clinical pathology department and Mansoura Research center for cord stem cells (MARC_CSC), Faculty of medicine, Mansura University, Mansoura, Egypt
| | - Doaa M Salah
- Pediatric Department, Pediatric Nephrology Unit & Kidney Transplantation Unit, Cairo University Children Hospital, Kasr Al-Ainy Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Ayman Hammad
- Pediatric Nephrology Unit, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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4
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Chen Y, Wang P, Zhang Y, Du XY, Zhang YJ. Comparison of effects of aminosalicylic acid, glucocorticoids and immunosuppressive agents on the expression of multidrug-resistant genes in ulcerative colitis. Sci Rep 2022; 12:20656. [PMID: 36450761 PMCID: PMC9712546 DOI: 10.1038/s41598-022-19612-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 08/31/2022] [Indexed: 12/05/2022] Open
Abstract
To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressants on the expression levels of multidrug resistance genes in patients with ulcerative colitis (UC), with the aim of providing a theoretical and therapeutic basis for the diagnosis, treatment, and prevention of UC. Fresh colonic mucosal tissues or postoperative pathological biopsies from 148 UC patients were collected, and the distribution sites and morphology of P-glycoprotein (P-gp) were detected using immunohistochemical staining. RT-PCR was used to quantify the expression levels of multidrug resistance gene (MDR1) mRNA before and after the corresponding treatment, and the effects of aminosalicylic acid, glucocorticoids and immunosuppressive drugs on P-gp were compared. In addition, the effects of the three drugs on MDR1 mRNA were analyzed. Administration of 5-aminosalicylic acid (5-ASA) drugs did not correlate with MDR1 expression in UC, whereas administration of glucocorticoids and immunosuppressive drugs was positively correlated with MDR1 expression profile. The expression levels of MDR1 mRNA and its product P-gp were significantly upregulated in patients who did not respond to glucocorticoids and immunosuppressive drugs. 5-ASA had no effect on the expression levels of MDR1 and its product P-gp in patients with a confirmed diagnosis of UC. However, the use of glucocorticoids and immunosuppressants can increase the expression level of MDR1.
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Affiliation(s)
- Yan Chen
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
| | - Ping Wang
- grid.453074.10000 0000 9797 0900Department of Public Health, School of Medicine, Henan University of Science and Technology, Luoyang, 471003 Henan China
| | - Yin Zhang
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
| | - Xiao-Yu Du
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
| | - Ying-Jian Zhang
- grid.453074.10000 0000 9797 0900Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, 471003 Henan China
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Research advances in the role and pharmaceuticals of ATP-binding cassette transporters in autoimmune diseases. Mol Cell Biochem 2022; 477:1075-1091. [PMID: 35034257 DOI: 10.1007/s11010-022-04354-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/06/2022] [Indexed: 10/19/2022]
Abstract
Autoimmune diseases are caused by the immune response of the body to its antigens, resulting in tissue damage. The pathogenesis of these diseases has not yet been elucidated. Most autoimmune diseases cannot be cured by effective drugs. The treatment strategy is to relieve the symptoms of the disease and balance the body's autoimmune function. The abnormal expression of ATP-binding cassette (ABC) transporters is directly related to the pathogenesis of autoimmune diseases and drug therapy resistance, which poses a great challenge for the drug therapy of autoimmune diseases. Therefore, this paper reviews the interplay between ABC transporters and the pathogenesis of autoimmune diseases to provide research progress and new ideas for the development of drugs in autoimmune diseases.
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Petryszyn P, Dudkowiak R, Gruca A, Jaźwińska-Tarnawska E, Ekk-Cierniakowski P, Poniewierka E, Wiela-Hojeńska A, Głowacka K. C3435T Polymorphism of the ABCB1 Gene in Polish Patients with Inflammatory Bowel Disease: A Case-Control and Meta-Analysis Study. Genes (Basel) 2021; 12:genes12091419. [PMID: 34573401 PMCID: PMC8465101 DOI: 10.3390/genes12091419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 12/30/2022] Open
Abstract
P-glycoprotein encoded by the ABCB1 gene constitutes a molecular barrier in the small and large bowel epithelium, and its different expression may influence susceptibility to inflammatory bowel disease (IBD). We aimed to assess the contribution of the C3435T polymorphism to disease risk in the Polish population. A total of 100 patients (50 Crohn's disease (CD), 50 ulcerative colitis (UC)) and 100 healthy controls were genotyped for the single nucleotide polymorphism (SNP) C3435T by using the PCR-RFLP method. Patients were classified on the basis of disease phenotype and the specific treatment used. A meta-analysis was carried out of our results and those from previously published Polish studies. There was no significant difference in allele and genotype frequencies in IBD patients compared with controls. For CD patients, a lower frequency of TT genotype in those with colonic disease, a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease were observed, whereas for UC patients, a lower frequency of CT genotype was observed in those with left-sided colitis. A meta-analysis showed a tendency towards higher prevalence of CC genotype in UC cases. These results indicate that the C3435T variants may confer a risk for UC and influence disease behaviour.
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Affiliation(s)
- Paweł Petryszyn
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
- Correspondence: ; Tel.: +48-717840601
| | - Robert Dudkowiak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Agnieszka Gruca
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Ewa Jaźwińska-Tarnawska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | | | - Elżbieta Poniewierka
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Anna Wiela-Hojeńska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Krystyna Głowacka
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
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Jala A, Ponneganti S, Vishnubhatla DS, Bhuvanam G, Mekala PR, Varghese B, Radhakrishnanand P, Adela R, Murty US, Borkar RM. Transporter-mediated drug-drug interactions: advancement in models, analytical tools, and regulatory perspective. Drug Metab Rev 2021; 53:285-320. [PMID: 33980079 DOI: 10.1080/03602532.2021.1928687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/05/2021] [Indexed: 02/08/2023]
Abstract
Drug-drug interactions mediated by transporters are a serious clinical concern hence a tremendous amount of work has been done on the characterization of the transporter-mediated proteins in humans and animals. The underlying mechanism for the transporter-mediated drug-drug interaction is the induction or inhibition of the transporter which is involved in the cellular uptake and efflux of drugs. Transporter of the brain, liver, kidney, and intestine are major determinants that alter the absorption, distribution, metabolism, excretion profile of drugs, and considerably influence the pharmacokinetic profile of drugs. As a consequence, transporter proteins may affect the therapeutic activity and safety of drugs. However, mounting evidence suggests that many drugs change the activity and/or expression of the transporter protein. Accordingly, evaluation of drug interaction during the drug development process is an integral part of risk assessment and regulatory requirements. Therefore, this review will highlight the clinical significance of the transporter, their role in disease, possible cause underlying the drug-drug interactions using analytical tools, and update on the regulatory requirement. The recent in-silico approaches which emphasize the advancement in the discovery of drug-drug interactions are also highlighted in this review. Besides, we discuss several endogenous biomarkers that have shown to act as substrates for many transporters, which could be potent determinants to find the drug-drug interactions mediated by transporters. Transporter-mediated drug-drug interactions are taken into consideration in the drug approval process therefore we also provided the extrapolated decision trees from in-vitro to in-vivo, which may trigger the follow-up to clinical studies.
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Affiliation(s)
- Aishwarya Jala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Srikanth Ponneganti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Devi Swetha Vishnubhatla
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Gayathri Bhuvanam
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Prithvi Raju Mekala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Bincy Varghese
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Pullapanthula Radhakrishnanand
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Ramu Adela
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | | | - Roshan M Borkar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
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Huang X, Sun W, Yan Z, Shi H, Yang Q, Wang P, Li S, Liu L, Zhao S, Gun S. Integrative Analyses of Long Non-coding RNA and mRNA Involved in Piglet Ileum Immune Response to Clostridium perfringens Type C Infection. Front Cell Infect Microbiol 2019; 9:130. [PMID: 31114763 PMCID: PMC6503642 DOI: 10.3389/fcimb.2019.00130] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 04/12/2019] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have been shown to play important roles in regulating host immune and inflammatory responses to bacterial infection. Infection with Clostridium perfringens (C. perfringens), a food-borne zoonotic pathogen, can lead to a series of inflammatory diseases in human and piglet, greatly challenging the healthy development of global pig industry. However, the roles of lncRNAs involved in piglet immune response against C. perfringens type C infection remain unknown. In this study, the regulatory functions of ileum lncRNAs and mRNAs were investigated in piglet immune response to C. perfringens type C infection among resistance (IR), susceptibility (IS) and sham-inoculation (control, IC) groups. A total of 480 lncRNAs and 3,669 mRNAs were significantly differentially expressed, the differentially expressed lncRNAs and mRNAs in the IR and IS groups were enriched in various pathways of ABC transporters, olfactory transduction, PPAR signaling pathway, chemokine signaling pathway and Toll-like receptor signaling pathway, involving in regulating piglet immune responses and resistance during infection. There were 212 lncRNAs and 505 target mRNAs found to have important association with C. perfringens infectious diseases, furthermore, 25 dysregulated lncRNAs corresponding to 13 immune-related target mRNAs were identified to play potential roles in defense against bacterial infection. In conclusion, the results improve our understanding on the characteristics of lncRNAs and mRNAs on regulating host immune response against C. perfringens type C infection, which will provide a reference for future research into exploring C. perfringens-related diseases in human.
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Affiliation(s)
- Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Wenyang Sun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Zunqiang Yan
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Hairen Shi
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Shenggui Li
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Lixia Liu
- College of Life Science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Shengguo Zhao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China.,Gansu Research Center for Swine Production Engineering and Technology, Lanzhou, China
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Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function. Cells 2019; 8:cells8020193. [PMID: 30813280 PMCID: PMC6407030 DOI: 10.3390/cells8020193] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 02/18/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023] Open
Abstract
The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation.
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10
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ABC transporters Mdr1a/1b, Bcrp1, Mrp2 and Mrp3 determine the sensitivity to PhIP/DSS-induced colon carcinogenesis and inflammation. Arch Toxicol 2019; 93:775-790. [DOI: 10.1007/s00204-019-02394-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/10/2019] [Indexed: 12/29/2022]
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Mijac D, Vukovic-Petrovic I, Mijac V, Perovic V, Milic N, Djuranovic S, Bojic D, Popovic D, Culafic D, Krstic M, Jankovic G, Pravica V, Markovic M. MDR1 gene polymorphisms are associated with ulcerative colitis in a cohort of Serbian patients with inflammatory bowel disease. PLoS One 2018; 13:e0194536. [PMID: 29543864 PMCID: PMC5854418 DOI: 10.1371/journal.pone.0194536] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 03/05/2018] [Indexed: 12/12/2022] Open
Abstract
Background Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology in which genetic factors contribute to development of disease. Single nucleotide polymorphisms (SNPs) in multidrug resistance 1 (MDR1) gene encoding transporter P-glycoprotein have been associated with IBD, but their role in disease susceptibility remains unclear. Therefore, the aim of this study was to investigate the association of three MDR1 polymorphisms, C1236T (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642), with Serbian IBD patients. Methods A total of 206 IBD patients, 107 Crohn's disease (CD) and 99 ulcerative colitis (UC), and 255 healthy controls were included in the study. All subjects were genotyped using TaqMan SNP genotyping assays. Comparisons between the groups were performed using the Pearson Chi-square test. False discovery rate according to Benjamini-Hochberg procedure was applied to adjust for multiple comparisons. Results Carriers of T allele of all three MDR1 SNPs were more common in UC patients compared to healthy controls, suggesting predisposing role of T allele of these SNPs in UC pathogenesis. Consistently, TT genotype of C1236T and TTT haplotype were also found more frequently in UC patients. On the other hand, C allele and CC genotype of C1236T and C3435T, as well as G allele and GG genotype of G2677T/A were more frequent in healthy subjects, implying protective role of these variants in UC. Likewise, CGC haplotype and CGC/CGC diplotype were more frequent in controls. Contrary to UC, no statistical difference was observed between CD patients and controls in any of the SNPs analyzed. Conclusion MDR1 gene variants and haplotypes were associated with UC in Serbian IBD patients, further supporting their potential role in susceptibility to UC.
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Affiliation(s)
- Dragana Mijac
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
- * E-mail:
| | - Irena Vukovic-Petrovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vera Mijac
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladimir Perovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Natasa Milic
- Department for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States of America
| | - Srdjan Djuranovic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Daniela Bojic
- Department of Gastroenterology, University Hospital Zvezdara, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragan Popovic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Djordje Culafic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Miodrag Krstic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Goran Jankovic
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Clinical Center of Serbia, Belgrade, Serbia
| | - Vera Pravica
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milos Markovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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12
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Ho GT, Aird RE, Liu B, Boyapati RK, Kennedy NA, Dorward DA, Noble CL, Shimizu T, Carter RN, Chew ETS, Morton NM, Rossi AG, Sartor RB, Iredale JP, Satsangi J. MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunol 2018; 11:120-130. [PMID: 28401939 PMCID: PMC5510721 DOI: 10.1038/mi.2017.31] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 02/14/2017] [Accepted: 03/01/2017] [Indexed: 02/04/2023]
Abstract
The multidrug resistance-1 (MDR1) gene encodes an ATP-dependent efflux transporter that is highly expressed in the colon. In mice, loss of MDR1 function results in colitis with similarities to human inflammatory bowel diseases (IBD). Here, we show that MDR1 has an unexpected protective role for the mitochondria where MDR1 deficiency results in mitochondrial dysfunction with increased mitochondrial reactive oxygen species (mROS) driving the development of colitis. Exogenous induction of mROS accelerates, while inhibition attenuates colitis in vivo; these effects are amplified in MDR1 deficiency. In human IBD, MDR1 is negatively correlated to SOD2 gene expression required for mROS detoxification. To provide direct evidential support, we deleted intestinal SOD2 gene in mice and showed an increased susceptibility to colitis. We exploited the genome-wide association data sets and found many (∼5%) of IBD susceptibility genes with direct roles in regulating mitochondria homeostasis. As MDR1 primarily protects against xenotoxins via its efflux function, our findings implicate a distinct mitochondrial toxin+genetic susceptibility interaction leading to mitochondrial dysfunction, a novel pathogenic mechanism that could offer many new therapeutic opportunities for IBD.
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Affiliation(s)
- Gwo-Tzer Ho
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
- Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Rhona E Aird
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Bo Liu
- Departments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599-7032, USA
| | - Ray K Boyapati
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
- Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Nicholas A Kennedy
- Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - David A Dorward
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Colin L Noble
- Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Takahiko Shimizu
- Department of Advanced Aging Medicine, University of Chiba, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Roderick N Carter
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Etienne TS Chew
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Nicholas M Morton
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Adriano G Rossi
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - R. Balfour Sartor
- Departments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599-7032, USA
| | - John P Iredale
- MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
- University of Bristol, Bristol BS8 1TH, UK
| | - Jack Satsangi
- Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
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13
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Borecki K, Zawada I, Pawinska-Matecka A, Salkic NN, Karakiewicz B, Adler G. ABCB1 3435C>T and 2677G>T/A polymorphisms in Polish and Bosnian patients with Crohn's disease - A preliminary report. Bosn J Basic Med Sci 2017; 17:323-327. [PMID: 28759738 DOI: 10.17305/bjbms.2017.2172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/04/2017] [Accepted: 07/04/2017] [Indexed: 11/16/2022] Open
Abstract
The role of ABCB1 single nucleotide polymorphisms (SNPs) in the development of Crohn's disease (CD) remains unclear. Due to inconsistent results of several European population-based studies and limited information on populations from Poland and Bosnia and Herzegovina (B&H), we conducted a preliminary association study of two main ABCB1 SNPs and CD. ABCB1 3435C>T and 2677G>T/A SNPs were analyzed in Polish and Bosnian patients with CD (n = 85 and n = 30, respectively) and controls (n = 82 and n = 30, respectively) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 3435C>T and allele-specific PCR for 2677G>A/T SNP. A deviation from Hardy-Weinberg equilibrium was found for both SNPs in Polish patients with CD, and for 2677G>A/T in Polish control group. The allele and genotype frequencies of the two ABCB1 SNPs were not significantly different between the CD patients and controls in both populations (p > 0.05). Similarly, the genotype distribution of 3435C>T and 2677G>T/A SNPs was not significantly different between Polish and Bosnian patients with CD (p > 0.05). At least one mutated ABCB1 allele was carried by 97.7% of Polish and 90.0% of Bosnian patients with CD. No association was found between the ABCB1 SNPs and CD in the two populations. In conclusion, the two ABCB1 SNPs may not contribute to CD susceptibility in the populations of Poland and B&H. Further studies with larger samples in both populations are warranted.
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Affiliation(s)
- Krzysztof Borecki
- Department of Gerontobiology, Pomeranian Medical University, Szczecin, Poland.
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14
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Wang J, Liu Y, Zhao J, Xu J, Li S, Qin X. P-glycoprotein gene MDR1 polymorphisms and susceptibility to systemic lupus erythematosus in Guangxi population: a case-control study. Rheumatol Int 2017; 37:537-545. [PMID: 28154898 DOI: 10.1007/s00296-017-3652-2] [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] [Received: 08/07/2016] [Accepted: 01/10/2017] [Indexed: 02/06/2023]
Abstract
The multidrug resistance 1 gene (MDR1) encodes for P-glycoprotein (P-gp), which plays a pathophysiological role in the development of autoimmune diseases, including systemic lupus erythematosus (SLE). Herein, we aimed to investigate the relationship between MDR1 gene polymorphisms and SLE susceptibility in the Chinese Guangxi population. The genotypes of rs1128503 and rs1045642 in MDR1 gene were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method in 283 SLE patients and 247 healthy controls from Guangxi. Direct sequencing method was used to verify the results. Binary logistic regression analyses adjusting for gender and age indicated that subjects carrying the rs1128503 T-allele and TT genotype were at increased risk of SLE when compared to carriers of the C allele and CC genotype, with adjusted ORs of 1.36 (95% CI 1.07-1.74; P = 0.014) and 1.77 (95% CI 1.08-2.88; P = 0.022), respectively. In addition, the risk allele T had a recessive effect (OR 1.49, 95% CI 1.04-2.14, P = 0.029). Subgroup analyses revealed effect modification by age for the presence of the rs1128503 T allele, yielding a significant positive association with SLE in older (≥40 years) subjects (T vs. C allele: OR 1.41, 95% CI 1.01-1.96; P = 0.041; TT vs. CC genotype: OR 1.74, 95% CI 1.07-2.79; P = 0.021). For the first time, we demonstrated that MDR1 rs1128503 polymorphisms were associated with SLE susceptibility in Chinese Guangxi population.
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Affiliation(s)
- Jian Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yanqiong Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jiangyang Zhao
- Department of Clinical Laboratory, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Juanjuan Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shan Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| | - Xue Qin
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
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15
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Bouzidi A, Mesbah-Amroun H, Boukercha A, Benhassine F, Belboueb R, Berkouk K, Messadi W, Touil-Boukoffa C. Association between MDR1 gene polymorphisms and the risk of Crohn's disease in a cohort of Algerian pediatric patients. Pediatr Res 2016; 80:837-843. [PMID: 27603561 DOI: 10.1038/pr.2016.163] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 06/21/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND The multi-drug resistance gene (MDR1) has raised increasing interest as a susceptibility gene for Crohn's disease (CD). The role of MDR1 single-nucleotide polymorphisms (SNPs) in the predisposition and behavior of CD in the pediatric population is still elusive. Here, we investigated whether SNPs in MDR1 are associated with CD in Algerian pediatric patients. METHODS A case-control study was conducted enrolling 47 pediatric CD patients and 100 controls. All subjects were genotyped for the most common MDR1 SNPs (C3434T, C1236T, and G2677A/T) using PCR-RFLP method. We also explored the association between polymorphisms and clinical sub-phenotypes. RESULTS We have detected no significant association of C3435T SNP and pediatric CD. However, we observed a significantly higher frequency of the risk alleles, 1236T and 2677T/A among the CD patients compared to controls. Moreover, the risk allele 1236T was associated to a higher risk for resective surgery. CONCLUSION Our data suggest that the C1236T and G2677A/T SNPs in the MDR1 gene are associated with CD and the C1236T risk allele with a more severe course of disease in Algerian pediatric patients. Further analysis using larger patients group and functional studies would be interesting to elucidate the role of MDR1 gene in pediatric CD.Pediatric Research (2016); doi:10.1038/pr.2016.163.
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Affiliation(s)
- Amira Bouzidi
- Department of Cellular and Molecular Biology, Cytokines and NO Synthases -Immunity and Pathogeny Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | - Hamida Mesbah-Amroun
- Department of Cellular and Molecular Biology, Cytokines and NO Synthases -Immunity and Pathogeny Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | - Aziza Boukercha
- Department of Cellular and Molecular Biology, Cytokines and NO Synthases -Immunity and Pathogeny Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | | | - Réda Belboueb
- Department of Pediatrics, University Hospital Center Mustapha Bacha, Algiers, Algeria
| | - Karima Berkouk
- Department of Pediatrics, University Hospital Center Lamine Debaghine, Algiers, Algeria
| | - Wassila Messadi
- Department of Pediatrics, University Hospital Center Issaad Hassani, Algiers, Algeria
| | - Chafia Touil-Boukoffa
- Department of Cellular and Molecular Biology, Cytokines and NO Synthases -Immunity and Pathogeny Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
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16
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van der Weide K, Loovers H, Pondman K, Bogers J, van der Straaten T, Langemeijer E, Cohen D, Commandeur J, van der Weide J. Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population. THE PHARMACOGENOMICS JOURNAL 2016; 17:471-478. [PMID: 27168101 DOI: 10.1038/tpj.2016.32] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 02/03/2016] [Accepted: 04/15/2016] [Indexed: 12/21/2022]
Abstract
Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1null (glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P=0.05 and 31% versus 14%, P=0.03), whereas GSTM1null was less frequent in these patients (31% versus 52%, P=0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case-control study.
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Affiliation(s)
- K van der Weide
- Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands
| | - H Loovers
- Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.,Psychiatric Hospital GGz Centraal, Dependance Meerkanten, Ermelo, The Netherlands
| | - K Pondman
- Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands
| | - J Bogers
- Mental Health Services Rivierduinen, Oegstgeest, The Netherlands
| | - T van der Straaten
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - E Langemeijer
- Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - D Cohen
- Mental Health Services North-Holland North, Heerhugowaard, The Netherlands
| | - J Commandeur
- AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU Amsterdam, Amsterdam, The Netherlands
| | - J van der Weide
- Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.,Psychiatric Hospital GGz Centraal, Dependance Meerkanten, Ermelo, The Netherlands
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17
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Saadati HR, Wittig M, Helbig I, Häsler R, Anderson CA, Mathew CG, Kupcinskas L, Parkes M, Karlsen TH, Rosenstiel P, Schreiber S, Franke A. Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci. BMC MEDICAL GENETICS 2016; 17:26. [PMID: 27037036 PMCID: PMC4818401 DOI: 10.1186/s12881-016-0289-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 03/23/2016] [Indexed: 12/30/2022]
Abstract
Background Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. Methods One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication. Results Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43 % cases, 0.11 % controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13 % cases, 0.01 % controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22 % carriers among cases, 0.03 % carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation. Conclusion Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0289-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hamid Reza Saadati
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Michael Wittig
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Ingo Helbig
- Department of Neuropediatrics, University Clinic Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, Building 9, 24105, Kiel, Germany
| | - Robert Häsler
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Carl A Anderson
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
| | - Christopher G Mathew
- Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Mickeviciaus 9, Kaunas, LT, 44307, Lithuania
| | - Miles Parkes
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital, Rikshospitalet, 0027, Oslo, Norway
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.,Department of Internal Medicine, University Hospital Schleswig-Holstein, Schittenhelmstraße 12, 24105, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.
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18
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ADLER G, PAWIŃSKA-MATECKA A, GARSTKA A, SALKIC NN, VALJEVAC A, KARAKIEWICZ B. First report on the distribution of 3435C>T ABCB1/MDR1polymorphism in healthy Bosniak population. Turk J Med Sci 2016; 46:942-4. [DOI: 10.3906/sag-1410-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Accepted: 07/27/2015] [Indexed: 11/03/2022] Open
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19
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Gómez-Gómez GJ, Masedo &A, Yela C, Martínez-Montiel MDP, Casís B. Current stage in inflammatory bowel disease: What is next? World J Gastroenterol 2015; 21:11282-11303. [PMID: 26525013 PMCID: PMC4616205 DOI: 10.3748/wjg.v21.i40.11282] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/12/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.
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20
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Genetic Polymorphisms of Multidrug Resistance Gene-1 (MDR1/ABCB1) and Glutathione S-Transferase Gene and the Risk of Inflammatory Bowel Disease among Moroccan Patients. Mediators Inflamm 2015; 2015:248060. [PMID: 26604430 PMCID: PMC4641206 DOI: 10.1155/2015/248060] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/06/2015] [Accepted: 09/08/2015] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are multifactorial disorders resulting from environmental and genetic factors. Polymorphisms in MDR1 and GSTs genes might explain individual differences in susceptibility to IBD. We carried out a case-control study to examine the association of MDR1 (C1236T and C3435T), GSTT1, and GSTM1 polymorphisms with the risk of IBD. Subjects were genotyped using PCR-RFLP for MDR1 gene and multiplex PCR for GSTT1 and GSTM1. Meta-analysis was performed to test the association of variant allele carriage with IBD risk. We report that GSTT1 null genotype is significantly associated with the risk of CD (OR: 2.5, CI: 1.2–5, P = 0.013) and UC (OR: 3.5, CI: 1.5–8.5, P = 0.004) and can influence Crohn's disease behavior. The interaction between GSTT1 and GSTM1 genes showed that the combined null genotypes were associated with the risk of UC (OR: 3.1, CI: 1.1–9, P = 0.049). Furthermore, when compared to combined 1236CC/CT genotypes, the 1236TT genotype of MDR1 gene was associated with the risk of UC (OR: 3.7, CI: 1.3–10.7, P = 0.03). Meta-analysis demonstrated significantly higher frequencies of 3435T carriage in IBD patients. Our results show that GSTT1 null and MDR1 polymorphisms could play a role in susceptibility to IBD.
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21
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Majumder K, Liang G, Chen Y, Guan L, Davidge ST, Wu J. Egg ovotransferrin-derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats. Mol Nutr Food Res 2015; 59:1735-44. [PMID: 26016560 PMCID: PMC5034750 DOI: 10.1002/mnfr.201500050] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 04/23/2015] [Accepted: 04/29/2015] [Indexed: 12/31/2022]
Abstract
Scope Egg ovotransferrin‐derived angiotensin converting enzyme (ACE) inhibitory peptide IRW was previously shown to reduce blood pressure in spontaneously hypertensive rats through reduced vascular inflammation and increased nitric oxide‐mediated vasorelaxation. The main objective of the present study was to investigate the molecular mechanism of this peptide through transcriptome analysis by RNAseq technique. Methods and results Total RNA was extracted from kidney and mesenteric arteries; the RNAseq libraries (from untreated and IRW‐treated groups) were constructed and subjected to sequence using HiSeq 2000 system (Illumina) system. A total of 12 764 and 13 352 genes were detected in kidney and mesenteric arteries, respectively. The differentially expressed (DE) genes between untreated and IRW‐treated groups were identified and the functional analysis through ingenuity pathway analysis revealed a greater role of DE genes identified from mesenteric arteries than that of kidney in modulating various cardiovascular functions. Subsequent qPCR analysis further confirmed that IRW significantly increased the expression of ACE‐2, ABCB‐1, IRF‐8, and CDH‐1 while significantly decreased the expression ICAM‐1 and VCAM‐1 in mesenteric arteries. Conclusion Our research showed for the first time that ACE inhibitory peptide IRW could contribute to its antihypertensive activity through increased ACE2 and decreased proinflammatory genes expression.
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Affiliation(s)
- Kaustav Majumder
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada.,Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
| | - Guanxiang Liang
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada
| | - Yanhong Chen
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada
| | - LeLuo Guan
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada
| | - Sandra T Davidge
- Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.,Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada.,Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada.,Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
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22
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Jaźwińska-Tarnawska E, Jęśkowiak I, Waszczuk E, Mulak A, Głowacka K, Hurkacz M, Paradowski L, Zaleska Z, Wiela-Hojeńska A. Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency? Pharmacol Rep 2014; 67:294-8. [PMID: 25712653 DOI: 10.1016/j.pharep.2014.09.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 09/28/2014] [Accepted: 09/30/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND In recent years, an increasing incidence of inflammatory bowel disease (IBD) has been reported, mainly as Crohn's disease (CD) and ulcerative colitis (UC). The individual susceptibility, the disease's course and response to the applied therapy is likely due to genetic factors such as ABCB1 gene mutations, exemplified by C3435T polymorphism. The aim of the study was to evaluate the distribution of C3435T polymorphism regarding the gender in IBD patients and control subjects from Lower Silesia region and its possible association with IBD susceptibility. METHODS The research was conducted in groups of 61 IBD patients and 101 healthy subjects from the Lower Silesia region. Polymorphism of C3435T was determined using PCR-RFLP method. RESULTS Frequency distributions of C3435T genotype and of 3435T or 3435C gene alleles of IBD, CD or UC patients were compared to control group; each treated as a whole or split further by gender. The statistically significant correlation was discovered between gender and C3435T genotype both for IBD and CD patients, with 3435CT heterozygote prevailing in IBD and CD males. Odds ratio calculations revealed statistically significant difference for the 3435CT genotype between control and: IBD group considered as a whole; IBD males; CD males; and for 3435TT variant between control and IBD males. Conclusions. The 3435CT genotype could be a risk factor for IBD and CD in men. The 3435TT genotype in males seems to be associated with the lower chance of IBD presence.
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Affiliation(s)
| | - Izabela Jęśkowiak
- Department of Clinical Pharmacology Wroclaw Medical University, Wrocław, Poland
| | - Ewa Waszczuk
- Department of Gastroenterology and Hepatology Wroclaw Medical University, Wrocław, Poland
| | - Agata Mulak
- Department of Gastroenterology and Hepatology Wroclaw Medical University, Wrocław, Poland
| | - Krystyna Głowacka
- Department of Clinical Pharmacology Wroclaw Medical University, Wrocław, Poland.
| | - Magdalena Hurkacz
- Department of Clinical Pharmacology Wroclaw Medical University, Wrocław, Poland
| | - Leszek Paradowski
- Department of Gastroenterology and Hepatology Wroclaw Medical University, Wrocław, Poland
| | - Zofia Zaleska
- Department of Clinical Pharmacology Wroclaw Medical University, Wrocław, Poland
| | - Anna Wiela-Hojeńska
- Department of Clinical Pharmacology Wroclaw Medical University, Wrocław, Poland.
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Sarlos P, Kovesdi E, Magyari L, Banfai Z, Szabo A, Javorhazy A, Melegh B. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature. World J Gastrointest Pathophysiol 2014; 5:304-21. [PMID: 25133031 PMCID: PMC4133528 DOI: 10.4291/wjgp.v5.i3.304] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/19/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.
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Wang J, Guo X, Yu S, Zhang J, Song J, Ji M, Cao Z, Wang J, Liu Y, Dong W. MDR1 C3435T polymorphism and inflammatory bowel disease risk: a meta-analysis. Mol Biol Rep 2014; 41:2679-85. [PMID: 24449364 DOI: 10.1007/s11033-014-3127-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 01/11/2014] [Indexed: 12/19/2022]
Abstract
The C3435T polymorphism of the multidrug resistance gene (MDR1) has been implicated in inflammatory bowel disease (IBD) risk, but the reported results are inconsistent. Here we performed a meta-analysis to evaluate the association between C3435T polymorphism and the risk of IBD using all case-control studies published before February 2013 according to PubMed and Web of Science. A total of 13 case-control studies, including 6,757 cases and 4,295 controls, were included. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the C3435T polymorphism was associated with the susceptibility to IBD (dominant model: OR = 1.05, 95 % CI: 0.96-1.16; CT vs. CC: OR = 1.06, 95 % CI: 0.95-1.17; TT vs. CC: OR = 1.04, 95 % CI: 0.92-1.17; recessive model: OR = 0.99, 95 % CI: 0.90-1.09). Besides, stratified analysis by clinical type also indicated that no significant association between MDR1 C3435T and the risk of Crohn's disease and ulcerative colitis was observed. This meta-analysis indicated that the C3435T polymorphism of MDR1 may not confer susceptibility to IBD.
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Affiliation(s)
- Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
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Carvalho ATP, Fróes RSB, Esberard BC, Santos JCVC, Rapozo DCM, Grinman AB, Simão TA, Nicolau Neto P, Luiz RR, Carneiro AJV, Souza HSPD, Ribeiro-Pinto LF. Multidrug resistance 1 gene polymorphisms may determine Crohn's disease behavior in patients from Rio de Janeiro. Clinics (Sao Paulo) 2014; 69:327-34. [PMID: 24838898 PMCID: PMC4012237 DOI: 10.6061/clinics/2014(05)06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/19/2013] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro. METHODS We analyzed 123 Crohn's disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn's disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations. RESULTS No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn's disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn's disease than in ulcerative colitis (p = 0.047). A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn's disease (OR: 4.13; p = 0.009), whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094). In Crohn's disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010). However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories. CONCLUSION The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn's disease. This association with Crohn's disease may support additional pathogenic roles for the multidrug resistance 1 gene in regulating gut-microbiota interactions and in mediating fibrosis. Understanding the effects of several drugs associated with multidrug resistance 1 gene variants may aid in the selection of customized therapeutic regimens.
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Affiliation(s)
- Ana Teresa P Carvalho
- Disciplina de Gastroenterologia e Endoscopia Digestiva, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Renata S B Fróes
- Disciplina de Gastroenterologia e Endoscopia Digestiva, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Barbara C Esberard
- Disciplina de Gastroenterologia e Endoscopia Digestiva, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Juliana C V C Santos
- Instituto Nacional de Câncer, Programa de Carcinogênese Molecular, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Davy C M Rapozo
- Instituto Nacional de Câncer, Programa de Carcinogênese Molecular, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Ana B Grinman
- Disciplina de Gastroenterologia e Endoscopia Digestiva, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Tatiana A Simão
- Laboratório de Toxicologia e Biologia Molecular, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Pedro Nicolau Neto
- Laboratório de Toxicologia e Biologia Molecular, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Ronir R Luiz
- Instituto de Epidemiologia e Saúde Coletiva, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Antonio José V Carneiro
- Departamento de Clínica Médica, Serviço de Gastroenterologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Heitor S P de Souza
- Departamento de Clínica Médica, Serviço de Gastroenterologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Luis Felipe Ribeiro-Pinto
- Laboratório de Toxicologia e Biologia Molecular, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
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Santos M, Carvalho S, Lima L, Nogueira A, Assis J, Mota-Pereira J, Pimentel P, Maia D, Correia D, Gomes S, Cruz A, Medeiros R. Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male Portuguese individuals. Genet Test Mol Biomarkers 2013; 18:12-9. [PMID: 24200053 DOI: 10.1089/gtmb.2013.0197] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Major depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus-pituitary-adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR)=0.360, 95% confidence interval [CI]: [0.140-0.950], p=0.022; C3435T: OR=0.306, 95% CI: [0.096-0.980], p=0.042; and G2677TA: OR=0.300, 95% CI: [0.100-0.870], p=0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR=0.313, 95% CI: [0.118-0.832], p=0.016, FDR p=0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.
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Affiliation(s)
- Marlene Santos
- 1 Molecular Oncology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology , Porto, Porto, Portugal
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Brinar M, Cukovic-Cavka S, Bozina N, Ravic KG, Markos P, Ladic A, Cota M, Krznaric Z, Vucelic B. MDR1 polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients. BMC Gastroenterol 2013; 13:57. [PMID: 23537364 PMCID: PMC3616873 DOI: 10.1186/1471-230x-13-57] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 03/18/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic diseases of unknown etiology and pathogenesis in which genetic factors contribute to development of disease. MDR1/ABCB1 is an interesting candidate gene for IBD. The role of two single nucleotide polymorphisms, C3435T and G2677T remains unclear due to contradictory results of current studies. Thus, the aims of this research were to investigate the association of MDR1 polymorphisms, C3435T and G2677T, and IBD. METHODS A total of 310 IBD patients, 199 Crohn's disease (CD) patients and 109 ulcerative colitis (UC) patients, and 120 healthy controls were included in the study. All subjects were genotyped for G2677T/A and C3435T polymorphism using RT-PCR. In IBD patients, review of medical records was performed and patients were phenotyped according to the Montreal classification. RESULTS Significantly higher frequency of 2677T allele (p=0.05; OR 1.46, 95% CI (1.0-2.14)) and of the 3435TT genotype was observed among UC patients compared to controls (p=0.02; OR 2.12; 95% CI (1.11-4.03). Heterozygous carriers for C3435T were significantly less likely to have CD (p=0.02; OR 0.58, 95% CI (0.36-0.91)). Haplotype analysis revealed that carriers of 3435T/2677T haplotype had a significantly higher risk of having UC (p=0.02; OR 1.55; 95% CI (1.06-2.28)). CONCLUSION MDR1 polymorphisms are associated with both CD and UC with a stronger association with UC.
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Affiliation(s)
- Marko Brinar
- Division of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb, 10000, Croatia.
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Tanner SM, Staley EM, Lorenz RG. Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis. Mucosal Immunol 2013; 6:309-23. [PMID: 22874899 PMCID: PMC3676969 DOI: 10.1038/mi.2012.73] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The FVB.mdr1a(-/-) mouse, lacking the small molecule pump P-glycoprotein (P-gp), is a commonly used model for the study of spontaneous T cell-mediated colitis. In addition, MDR1 polymorphisms and P-gp deficiency in humans have been linked to the development of ulcerative colitis. We now demonstrate that mice with P-gp deficiency have decreased levels of Foxp3(+) regulatory T cells (Tregs) in the intestinal lamina propria. This decrease is not due to either increased Treg apoptosis, altered Treg trafficking, or enhanced Treg plasticity to become Foxp3(+)IL-17(+) cells. Instead, P-gp deficiency appears to restrict the development of induced Treg cells (iTregs), as fewer Foxp3(+) iTregs developed from naive FVB.mdr1a(-/-) T cells both upon transforming growth factor-β (TGF-β) treatment in vitro and after adoptive transfer into FVB.rag2(-/-) recipients. Rather, in vitro TGF-β treatment results in a IL-17(+)CD4(+) T cell. This failure of iTregs to develop explains the decrease in Foxp3(+) Tregs in the FVB.mdr1a(-/-) intestine, representing a need to investigate this novel disease mechanism in human inflammatory bowel disease patients with MDR1 polymorphisms.
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Affiliation(s)
- Scott M. Tanner
- Department of Pathology at the University of Alabama at Birmingham
| | | | - Robin G. Lorenz
- Department of Pathology at the University of Alabama at Birmingham,Department of Microbiology at the University of Alabama at Birmingham
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Bonyadi MJ, Gerami SM, Somi MH, Khoshbaten M. Effect of the C3435T polymorphism of the multidrug resistance 1 gene on the severity of inflammatory bowel disease in Iranian Azeri Turks. Saudi J Gastroenterol 2013; 19:172-6. [PMID: 23828747 PMCID: PMC3745659 DOI: 10.4103/1319-3767.114515] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND/AIM Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a transmembrane efflux pump transferring both exogenous and endogenous substrate from the cells. In the human gastrointestinal tract, P-gp is found in high concentrations on the epithelial cells of the colon and small intestine. It is hypothesized that the expression level of MDR1 gene is related to susceptibility of both forms of inflammatory bowel disease (IBD). The aim of this study was to investigate the association of C3435T Single Nucleotide Polymorphism in IBD patients with/without clinical symptoms in Iranian Azeri Turks. SETTINGS AND DESIGN A total of 116 patients with IBD and 92 healthy subjects were analyzed. MATERIALS AND METHODS We investigated the distribution of MDR1 C3435T polymorphism via polymerase chain reaction - Restriction Fragment Length Polymorphism technique. STATISTICAL ANALYSIS USED All statistical analyses were calculated with the SPSS for Windows 16.0. The Fisher exact test was used to test for departure from Hardy-Weinberg equilibrium of the genotype frequencies ( P > 0.05). RESULTS The data showed that IBD patient with homozygous variant carrying MDR1 3435 T/T genotype has elevated risk for development of routine IBD clinical symptoms like Abdominal pain ( P = 0.005) and chronic Diarrhea ( P = 0.013) compared with MDR1 3435 C/C homozygotes who has reduced risk for development of IBD symptoms. CONCLUSIONS Our data showed that patients with MDR1 3435 T/T are more susceptible to the development of some routine IBD clinical symptoms ( P < 0.05). This study suggests a protective role for the MDR1 3435 C/C versus MDR1 3435 T/Tgenotype and C versus T allele for the progression of IBD in this cohort.
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Affiliation(s)
- Mortaza J. Bonyadi
- Liver and Gastrointestinal Disease Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran,Department of Biology, Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran,Address for correspondence: Dr. Mortaza Bonyadi, Liver and Gastrointestinal Disease Research Centre, Tabriz University of Medical Sciences and Department of Biology, Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran. E-mail:
| | - Sousan M. Gerami
- Liver and Gastrointestinal Disease Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad H. Somi
- Liver and Gastrointestinal Disease Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Manouchehr Khoshbaten
- Liver and Gastrointestinal Disease Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
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Dudarewicz M, Barańska M, Rychlik-Sych M, Trzciński R, Dziki A, Skrętkowicz J. C3435T polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population. Pharmacol Rep 2012; 64:343-50. [PMID: 22661185 DOI: 10.1016/s1734-1140(12)70774-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 12/13/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) belongs to the group of chronic diseases of the gastrointestinal tract, prevalence of which is increasing in the Polish population. The two main clinical types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). The expression level of the ABCB1/MDR1 gene which encodes P-glycoprotein seems to be of great prognostic relevance while evaluating patients' susceptibility to UC or CD. One of the most significant ABCB1/MDR1 gene mutations is the C3435T polymorphism. A decreased expression of the ABCB1/MDR1 gene and lower P-glycoprotein activity has been associated with the 3435T variant. The aim of the study was to evaluate the C3435T polymorphism in the IBD patients and to investigate a possible correlation with disease susceptibility. METHODS The study was performed on 108 patients with IBD and on 137 healthy individuals. All the participants were of Caucasian origin and came from central Poland. The C3435T polymorphism was analyzed by using the PCR-RFLP method. RESULTS Our results showed that ORs for IBD development (including UC and CD) were elevated in individuals both with the 3435CC genotype and the 3435C allele. The differences in genotype and allele frequencies were not significant. CONCLUSIONS The C3435T polymorphism of the ABCB1/MDR1 gene is not a risk factor for IBD, including UC and CD, in the population coming from central Poland.
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Affiliation(s)
- Michał Dudarewicz
- Department of Pharmacogenetics, Medical University of Lodz, Muszyńskiego 1, PL 90-151 Łódź, Poland
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Abstract
Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are chronically relapsing, immune-mediated disorders of the gastrointestinal tract. A major challenge in the treatment of IBD is the heterogenous nature of these pathologies. Both, ulcerative colitis and Crohn's disease are of multifactorial etiology and feature a complex interaction of host genetic susceptibility and environmental factors such as diet and gut microbiota. Genome-wide association studies identified disease-relevant single-nucleotide polymorphisms in approximately 100 genes, but at the same time twin studies also clearly indicated a strong environmental impact in disease development. However, attempts to link dietary factors to the risk of developing IBD, based on epidemiological observations showed controversial outcomes. Yet, emerging high-throughput technologies implying complete biological systems might allow taking nutrient-gene interactions into account for a better classification of patient subsets in the future. In this context, 2 new scientific fields, "nutrigenetics" and "nutrigenomics" have been established. "Nutrigenetics," studying the effect of genetic variations on nutrient-gene interactions and "Nutrigenomics," describing the impact of nutrition on physiology and health status on the level of gene transcription, protein expression, and metabolism. It is hoped that the integration of both research areas will promote the understanding of the complex gene-environment interaction in IBD etiology and in the long-term will lead to personalized nutrition for disease prevention and treatment. This review briefly summarizes data on the impact of nutrients on intestinal inflammation, highlights nutrient-gene interactions, and addresses the potential of applying "omic" technologies in the context of IBD.
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Staley EM, Yarbrough VR, Schoeb TR, Daft JG, Tanner SM, Steverson D, Lorenz RG. Murine P-glycoprotein deficiency alters intestinal injury repair and blunts lipopolysaccharide-induced radioprotection. Radiat Res 2012; 178:207-216. [PMID: 22780103 PMCID: PMC3474324 DOI: 10.1667/rr2835.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
P-glycoprotein (P-gp) has been reported to increase stem cell proliferation and regulate apoptosis. Absence of P-gp results in decreased repair of intestinal epithelial cells after chemical injury. To further explore the mechanisms involved in the effects of P-gp on intestinal injury and repair, we used the well-characterized radiation injury model. In this model, injury repair is mediated by production of prostaglandins (PGE(2)) and lipopolysaccharide (LPS) has been shown to confer radioprotection. B6.mdr1a(-/-) mice and wild-type controls were subjected to 12 Gy total body X-ray irradiation and surviving crypts in the proximal jejunum and distal colon were evaluated 3.5 days after irradiation. B6.mdr1a(-/-) mice exhibited normal baseline stem cell proliferation and COX dependent crypt regeneration after irradiation. However, radiation induced apoptosis was increased and LPS-induced radioprotection was blunted in the C57BL6.mdr1a(-/-) distal colon, compared to B6 wild-type controls. The LPS treatment induced gene expression of the radioprotective cytokine IL-1α, in B6 wild-type controls but not in B6.mdr1a(-/-) animals. Lipopolysaccharid-induced radioprotection was absent in IL-1R1(-/-) animals, indicating a role for IL-1α in radioprotection, and demonstrating that P-gp deficiency interferes with IL-1α gene expression in response to systemic exposure to LPS.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency
- Animals
- Apoptosis/drug effects
- Apoptosis/radiation effects
- Dinoprostone/metabolism
- Gene Expression Regulation, Enzymologic/drug effects
- Gene Expression Regulation, Enzymologic/radiation effects
- Immunity, Innate/drug effects
- Immunity, Innate/radiation effects
- Interleukin-1alpha/metabolism
- Intestines/drug effects
- Intestines/injuries
- Intestines/physiopathology
- Intestines/radiation effects
- Lipopolysaccharides/pharmacology
- Mice
- Mice, Inbred C57BL
- Prostaglandin-Endoperoxide Synthases/metabolism
- Radiation Injuries, Experimental/metabolism
- Radiation Injuries, Experimental/pathology
- Radiation Injuries, Experimental/physiopathology
- Radiation Injuries, Experimental/prevention & control
- Radiation-Protective Agents/pharmacology
- Regeneration/drug effects
- Regeneration/radiation effects
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Elizabeth M. Staley
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Vanisha R. Yarbrough
- Department of Cellular and Molecular Biology at Harvard University, Cambridge Massachusetts
| | - Trenton R. Schoeb
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joseph G. Daft
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Scott M. Tanner
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Dennis Steverson
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Robin G. Lorenz
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
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Fang K, Zhang S, Glawe J, Grisham MB, Kevil CG. Temporal genome expression profile analysis during t-cell-mediated colitis: identification of novel targets and pathways. Inflamm Bowel Dis 2012; 18:1411-23. [PMID: 22179924 PMCID: PMC4413946 DOI: 10.1002/ibd.22842] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 11/03/2011] [Indexed: 01/30/2023]
Abstract
BACKGROUND T cells critically regulate inflammatory bowel disease (IBD), with T-cell-dependent experimental colitis models gaining favor in identifying potential pathogenic mechanisms; yet limited understanding of specific pathogenic molecules or pathways still exists. METHODS In this study we sought to identify changes in whole genome expression profiles using the CD4CD45Rbhi T-cell transfer colitis model compared to genome expression differences from Crohn's disease (CD) tissue specimens. Colon tissue was used for histopathological and genome expression profiling analysis at 0, 2, 4, or 6 weeks after adoptive T-cell transfer. RESULTS We identified 1775 genes that were significantly altered during disease progression, with 361 being progressively downregulated and 341 progressively upregulated. Gene expression changes were validated by quantitative real-time polymerase chain reaction (qRT-PCR), confirming genome expression analysis data. Differentially expressed genes were clearly related to inflammation/immune responses but also strongly associated with metabolic, chemokine signaling, Jak-STAT signaling, and angiogenesis pathways. Ingenuity network analysis revealed 25 unique network associations that were associated with functions such as antigen presentation, cell morphology, cell-to-cell signaling and interaction, as well as nervous system development and function. Moreover, many of these genes and pathways were similarly identified in CD specimens. CONCLUSIONS These findings reveal novel, complex, and dynamic changes in gene expression that may provide useful targets for future therapeutic approaches.
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Affiliation(s)
- Kai Fang
- Department of Pathology, Louisiana State University Health Science Center, Shreveport, LA, 71103, USA
| | - Songlin Zhang
- Department of Pathology, Louisiana State University Health Science Center, Shreveport, LA, 71103, USA
| | - John Glawe
- Department of Pathology, Louisiana State University Health Science Center, Shreveport, LA, 71103, USA
| | - Matthew B. Grisham
- Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, 71103, USA
| | - Christopher G Kevil
- Department of Pathology, Louisiana State University Health Science Center, Shreveport, LA, 71103, USA,Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, 71103, USA,Corresponding author: Christopher G. Kevil, Ph.D., Department of Pathology, LSU Health Science Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71103, Phone: (318) 675-4694, Fax: (318) 675-7662,
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Stieger B, Meier PJ. Pharmacogenetics of drug transporters in the enterohepatic circulation. Pharmacogenomics 2012; 12:611-31. [PMID: 21619426 DOI: 10.2217/pgs.11.53] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.
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Affiliation(s)
- Bruno Stieger
- Division of Clinical Pharmacology & Toxicology, University Hospital, 8091 Zurich, Switzerland
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Zintzaras E, Song YB, Zheng WL, Jiang L, Ma WL. Is there evidence to claim or deny association between variants of the multidrug resistance gene (MDR1 or ABCB1) and inflammatory bowel disease? Inflamm Bowel Dis 2012; 18:562-72. [PMID: 21887726 DOI: 10.1002/ibd.21728] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 03/16/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a complex disease with a genetic background. Crohn's disease (CD) and ulcerative colitis (UC) are the two main types of IBD. There is indication that variants in the MDR1 gene are associated with development of IBD. However, the 20 published genetic association studies (GAS) for the three most popular variants in the MDR1 gene (C3435T, G2677T/A, and C1236T) have produced inclusive results. METHODS In order to decrease the uncertainty of pooled risk effects and to explore the trend and stability of the risk effects, a meticulous meta-analysis, including cumulative and recursive cumulative meta-analysis, of the GAS related to the MDR1 gene with susceptibility to IBD was conducted. The risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR(G) ). RESULTS The analysis showed marginal significant association for the C3435T variant in UC: the risk estimate for the allele contrast was OR = 1.11 (1.00-1.22) and OR(G) = 1.12 (1.01-1.27), indicating that a subject with high mutational load has a 12% higher probability of being diseased. The respective cumulative meta-analysis indicated a downward trend of association, as evidence accumulates with the association being significant during the whole published period. The cumulative meta-analysis for the other variants showed lack of any trend of association. However, the recursive cumulative meta-analysis showed that there is no sufficient evidence for denying or claiming an association for all variants. CONCLUSIONS More evidence is needed to draw safe conclusions regarding the association of MDR1 variants and development of IBD.
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Affiliation(s)
- Elias Zintzaras
- Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
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Umamaheswaran G, Krishna Kumar D, Kayathiri D, Rajan S, Shewade DG, Dkhar SA, Manjunath S, Ushakiran P, Reneega G, Ritushree K, Adithan C. Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population. Mol Biol Rep 2012; 39:6343-51. [PMID: 22318545 DOI: 10.1007/s11033-012-1456-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 01/23/2012] [Indexed: 01/18/2023]
Abstract
Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.
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Affiliation(s)
- Gurusamy Umamaheswaran
- ICMR Centre for Advance Research in Pharmacogenomics, Department of Pharmacology, JIPMER, Pondicherry, India.
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Silverton L, Dean M, Moitra K. Variation and evolution of the ABC transporter genes ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8: implication for pharmacogenetics and disease. ACTA ACUST UNITED AC 2011; 26:169-79. [PMID: 22098604 DOI: 10.1515/dmdi.2011.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The ATP-binding cassette (ABC) transporter genes are ubiquitous in the genomes of all vertebrates. Some of these transporters play a key role in xenobiotic defense and are endowed with the capacity to efflux harmful toxic substances. A major role in the evolution of the vertebrate ABC genes is played by gene duplication. Multiple gene duplication and deletion events have been identified in ABC genes, resulting in either gene birth or gene death indicating that the process of gene evolution is still ongoing in this group of transporters. Additionally, polymorphisms in these genes are linked to variations in expression, function, drug disposition and drug response. Single nucleotide polymorphisms in the ABC genes may be considered as markers of individual risk for adverse drug reactions or susceptibility to complex diseases as they can uniquely influence the quality and quantity of gene product. As the ABC genes continue to evolve, globalization will yield additional migration and racial admixtures that will have far reaching implications for the pharmacogenetics of this unique family of transporters in the context of human health.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP Binding Cassette Transporter, Subfamily G, Member 5
- ATP Binding Cassette Transporter, Subfamily G, Member 8
- ATP-Binding Cassette Transporters/genetics
- Animals
- Evolution, Molecular
- Genetic Variation
- Humans
- Lipoproteins/genetics
- Multidrug Resistance-Associated Proteins/genetics
- Neoplasm Proteins/genetics
- Pharmacogenetics
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Affiliation(s)
- Latoya Silverton
- Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA
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Sipeky C, Csongei V, Jaromi L, Safrany E, Maasz A, Takacs I, Beres J, Fodor L, Szabo M, Melegh B. Genetic Variability and Haplotype Profile of MDR1 (ABCB1) in Roma and Hungarian Population Samples with a Review of the Literature. Drug Metab Pharmacokinet 2011; 26:206-15. [DOI: 10.2133/dmpk.dmpk-10-sc-068] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Smith MA, Marinaki AM, Sanderson JD. Pharmacogenomics in the treatment of inflammatory bowel disease. Pharmacogenomics 2010; 11:421-37. [PMID: 20235796 DOI: 10.2217/pgs.10.4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In recent years, the benefits of early aggressive treatment paradigms for inflammatory bowel disease have emerged. Symptomatic improvement is no longer considered adequate; instead, the aim of treatment has become mucosal healing and altered natural history. Nonetheless, we still fail to achieve these end points in a large number of our patients. There are many reasons why patients fail to respond or develop toxicity when exposed to drugs used for inflammatory bowel disease, but genetic variation is likely to account for a significant proportion of this. Some examples, notably thiopurine methyltransferase polymorphism in thiopurine treatment, are already established in clinical practice. We present a review of the expanding literature in this field, highlighting many interesting developments in pharmacogenomics applied to inflammatory bowel disease and, where possible, providing guidance on the translation of these developments into clinical practice.
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Affiliation(s)
- Melissa A Smith
- Department of Gastroenterology, 1st Floor, College House, St Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK
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Ishihara S, Aziz MM, Yuki T, Kazumori H, Kinoshita Y. Inflammatory bowel disease: review from the aspect of genetics. J Gastroenterol 2010; 44:1097-108. [PMID: 19802731 DOI: 10.1007/s00535-009-0141-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2009] [Accepted: 09/09/2009] [Indexed: 02/04/2023]
Abstract
Regardless of how inflammatory bowel disease (IBD) is defined, the term "genetic susceptibility" is always included. Due to substantial progress in the characterization of susceptible genes that interact with environmental influences, a number of review articles offering the latest insights continue to be presented. To date, more than 30 novel IBD susceptible loci have been found, while several promising associations between IBD and gene variants have also been identified and replicated effectively. The present review highlights recent insights regarding linkage analysis and genome-wide association presented in studies of IBD susceptible genes, which provide additional evidence supporting their involvement in disease pathogenesis, based on linking to innate immune systems as a result of interactions with intestinal microbial flora. An improved understanding of IBD genetics will promote the identification of novel therapeutic agents, making it possible to identify environmental factors related to intestinal inflammation.
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Affiliation(s)
- Shunji Ishihara
- Department of Internal Medicine II, Faculty of Medicine, Shimane University School of Medicine, Izumo, Shimane, Japan.
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Ma MZ, Yang CM. Advances in understanding the correlation between multi-drug resistance gene and ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2009; 17:3530-3533. [DOI: 10.11569/wcjd.v17.i34.3530] [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 and pathogenesis of ulcerative colitis remain unclear. It has been reported that multiple drug resistant 1a (MDR 1a) knockout mice are susceptible to developing a spontaneous ulcerative colitis (UC). The incidence of C3435T gene mutation in the MDR1 gene in UC patients is significantly higher than that in healthy controls. The C3435T gene mutation can lead to decreased expression of P-glycoprotein (P-gp). The expression of P-gp in the peripheral blood lymphocytes and intestinal mucosal epithelial cells is higher in hormone-resistant UC patients than in hormone-sensitive UC patients and healthy controls. Thus, a hypothesis was proposed that the MDR1 gene polymorphism may correlate with the occurrence and progression of UC and the sensitivity to hormone therapy in UC patients. However, this hypothesis is still controversial.
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Huebner C, Browning BL, Petermann I, Han DY, Philpott M, Barclay M, Gearry R, McCulloch A, Demmers P, Ferguson LR. Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis. Inflamm Bowel Dis 2009; 15:1784-93. [PMID: 19685447 DOI: 10.1002/ibd.21019] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2008] [Accepted: 05/05/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) in the multidrug transporter MDR1 have been associated with inflammatory bowel disease (IBD) in different studies. However, the data are highly controversial. Recently, 6 haplotype tagging SNPs (tSNPs), representing the haplotype variations of the MDR1 gene, were identified. The aims of this study were to genotype these variants and correlate them to disease phenotype in New Zealand IBD patients. MATERIALS AND METHODS A total of 784 IBD patients and 200 healthy subjects were genotyped for 5 tSNPs and the triallelic MDR1 variant G2677T/A using the Sequenom MassArray platform. Furthermore, the effects of these variants were examined in correlation with phenotypic clinical features. RESULTS Heterozygous carriers for the variants C1236T, rs2235046 (an SNP in intron 16), and G2677T/A showed a lower risk of developing ulcerative colitis (C1236T: odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.42-0.93, P = 0.03; G2677T/A: OR = 0.59, CI = 0.39-0.89, P = 0.02; and rs2235046: OR = 0.59, 95% CI = 0.38-0.91, P = 0.009) as compared with homozygotes. None of the analyzed markers were associated with Crohn's disease on a genotypic level. Subgroup analysis revealed an association for 2 variants with IBD when stratified for age of onset (C1236T SNP and rs3789243). The MDR1 variant C3435T was associated with disease behavior in CD (OR = 1.45, 95% CI = 1.01-2.08, P = 0.04), whereas the SNP rs3789243 was found to be associated with pancolitis in UC patients (OR = 1.35, CI = 1.00-1.82, P = 0.05). CONCLUSIONS The results of our study support the role of MDR1 as a candidate gene for ulcerative colitis. Furthermore, our results suggest the possibility of a heterozygous advantage for certain MDR1 variants for this disease.
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Affiliation(s)
- Claudia Huebner
- Discipline of Nutrition, FM&HS, University of Auckland, Auckland, New Zealand.
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Cooney R, Cummings JRF, Pathan S, Beckly J, Geremia A, Hancock L, Guo C, Morris A, Jewell DP. Association between genetic variants in myosin IXB and Crohn's disease. Inflamm Bowel Dis 2009; 15:1014-21. [PMID: 19235913 DOI: 10.1002/ibd.20885] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Genetic variation in myosin IXB (MYO9B) was found to be associated with ulcerative colitis (UC) in a recent collaborative study. A nonsynonymous single nucleotide polymorphism (SNP) rs1545620 at the 3' end of the gene was found to be significantly associated with UC and weakly associated with Crohn's disease (CD). The aim of our current study was to replicate these findings in an independent UC cohort and to investigate association with CD. We also investigated subphenotype association and interactions with CARD15, IL23R, ATG16L1, and the IBD5 risk haplotype. METHODS In all, 652 CD patients, 650 UC patients, and 1190 controls were genotyped for 8 MYO9B SNPs. Haplotype testing, epistasis testing with known polymorphisms, and subphenotype analysis were performed. RESULTS An intronic SNP rs2305767 in the MYO9B gene was associated with inflammatory bowel disease (IBD) overall (corrected P-value 0.002, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.67-0.86). On individual disease analysis an association was found with CD (corrected P-value 0.001, OR 0.62, 95% CI 0.53-0.73) but not with UC. Analysis of the common MYO9B haplotypes showed significant association for CD and UC alone and IBD overall. No subphenotypic association was found. These data support an association between CD and SNPs in MYO9B independent of the established effects of SNPs in CARD15, IL23R, ATG16L1, and the IBD5 haplotype. There was no evidence of epistasis between SNPs in MYO9B and these established genes. CONCLUSIONS MYO9B variants may be involved in IBD pathogenesis.
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Affiliation(s)
- Rachel Cooney
- Wellcome Trust Centre of Human Genetics, University of Oxford, Oxford, UK.
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Abstract
The mechanism of inflammatory bowel disease (IBD) is partially understood, but it is certain that a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms, contributes to the pathogenesis of IBD. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. Those genes that have been consistently associated with IBD thus far primarily fall into one of three classes: those affecting bacterial recognition, those affecting immune response, and a third group affecting mucosal transport polarity or mucosal transporter function. This article reviews the IBD related genes mentioned above.
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Krupoves A, Seidman EG, Mack D, Israel D, Morgan K, Lambrette P, Costea I, Deslandres C, Grimard G, Law L, Levy E, Amre DK. Associations between ABCB1/MDR1 gene polymorphisms and Crohn's disease: a gene-wide study in a pediatric population. Inflamm Bowel Dis 2009; 15:900-8. [PMID: 19107781 DOI: 10.1002/ibd.20849] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Functional studies support the involvement of the MDR1 gene in the pathways leading to Crohn's disease (CD). Two common single nucleotide polymorphisms (SNPs), C3435T and G2677T/A, thought to alter the function of the corresponding P-glycoprotein, have shown inconsistent associations with CD. We investigated whether DNA variants in the MDR1 gene were associated with susceptibility for CD and specific phenotypes in children. METHODS A case-control study was conducted at 3 gastroenterology clinics across Canada. Children with CD and population- or hospital-based controls were included. CD cases were classified using the Montreal Classification. Thirteen tag-SNPs and the C3435T variant in the MDR1 gene were genotyped. Single-SNP allelic, genotype as well as gene-wide haplotype associations with CD and its phenotypes at diagnosis were assessed. RESULTS A total of 270 CD cases and 336 controls were studied. Most cases were male (56.3%), had disease location L3+/-L4 (58.1%), and an inflammatory phenotype B1+/-p (88.5%). Allelic association analysis revealed that SNP rs17327442 was significantly associated with overall susceptibility to CD (odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.50-0.99, P = 0.04) but this association did not withstand corrections for multiple testing (q-value = 0.56). Genotype-phenotype analysis indicated that 2 SNPs (rs10248420, P = 0.007, q-value = 0.07; rs2032583, P = 0.01, q-value = 0.07) were significantly associated with colonic disease. Five SNPs, rs1128503 (P = 0.02), rs1202184 (P = 0.008), rs1202186 (P = 0.02), rs2091766 (P = 0.03), and rs2235046 (P = 0.03) were nominally associated with noninflammatory CD. Specific haplotypes comprising of the tag-SNPs were significantly associated with either colonic or noninflammatory CD. CONCLUSIONS Our comprehensive gene-wide analysis suggests that the MDR1 gene may be associated with clinical phenotypes of CD in children.
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Staley EM, Schoeb TR, Lorenz RG. Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults. Inflamm Bowel Dis 2009; 15:684-96. [PMID: 19067430 PMCID: PMC2887754 DOI: 10.1002/ibd.20824] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND P-glycoprotein (P-gp), the product of the multidrug resistance gene (MDR), is an ATP-dependent transmembrane pump, which is expressed in multiple cell lineages including epithelial and hematopoetic cells. The human MDR gene is located on chromosome 7 (7q21.1), a susceptibility loci for inflammatory bowel disease (IBD). A significant number of IBD patients carry mutations in this gene and P-gp-deficient FVB/N mice develop a severe spontaneous colitis, characterized by impaired intestinal barrier function and immune reactivity to intestinal bacterial antigens. METHODS In this work we explored the role of mouse strain, as well as environmental insults, on the development of colonic inflammation in the absence of P-gp. Among the induction methods utilized, dextran sodium sulfate (DSS) disrupts the intestinal epithelium, while piroxicam is a nonsteroidal antiinflammatory (NSAID) drug that inhibits prostaglandin production and initiates colitis in IL10-deficient animals. Helicobacter bilis is a known mediator of bacterial-induced colitis. RESULTS We demonstrate that crossing this mutation onto the C57BL/6 strain confers protection from spontaneous colitis. C57BL/6.mdr1a-deficient animals demonstrated increased histological inflammation, colonic shortening, fecal blood, and reduced body weight after 7 days of treatment with 2.25% DSS. C57BL/6.mdr1a-deficient mice treated with piroxicam or infected with H. bilis showed no weight loss, or alterations in colonic histology. CONCLUSIONS These data indicate that the effects of P-gp deficiency are significantly modulated by background strain influences, but that the epithelium continues to have increased susceptibility to chemical injury in the C57BL/6 model.
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Affiliation(s)
| | | | - Robin G. Lorenz
- Department of Microbiology, University of Alabama at Birmingham,Department of Pathology, University of Alabama at Birmingham,Address correspondence to: Dr. Robin G. Lorenz, Department of Pathology, University of Alabama at Birmingham, 1825 University Blvd., SHEL 602, Birmingham, AL 35243-2182. Phone: 205-934-0676. Fax: 205-996-9113.
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Abstract
Crohn's disease and ulcerative colitis are chronic inflammatory disorders caused by a disruptive interaction between the immune system and gut luminal factors. Although the exact aetiology of IBD remains unclear, accumulating data, including genome-wide association studies (GWAS), have advanced our understanding of the immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis. It focuses on past and recent advances in our understanding of IBD, including genetics and immunobiology. Recently published GWAS have confirmed earlier findings related to the NOD2 gene and the IBD5 locus. In addition, over 30 novel loci have been identified. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal flora in the pathogenesis of inflammatory bowel disease.
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Affiliation(s)
- Casper G Noomen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, C4-12 Leiden, the Netherlands.
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Østergaard M, Ernst A, Labouriau R, Dagiliené E, Krarup HB, Christensen M, Thorsgaard N, Jacobsen BA, Tage-Jensen U, Overvad K, Autrup H, Andersen V. Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population. Scand J Gastroenterol 2009; 44:65-73. [PMID: 18819034 DOI: 10.1080/00365520802400826] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Crohn's disease (CD) and ulcerative colitis (UC) are characterized by an impaired mucosal defence to normal constituents of the intestinal flora and a dysregulated inflammatory response. The purpose of the study was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in these processes were associated with CD and UC. MATERIAL AND METHODS Allele frequencies of the cyclooxygenase 2 (COX-2/PTGS2/PGHS2) G-765C and breast cancer resistance protein (BCRP/ABCG2) C421A as well as allele and haplotype frequencies of multidrug resistance 1 (MDR1, ABCB1) SNPs G2677T/A, C3435T and G-rs3789243-A (intron 3) were assessed in a Danish case-control study comprising 373 CD and 541 UC patients and 796 healthy controls. RESULTS Carriers of the homozygous COX-2 and MDR1 intron 3 variant had a relatively high risk of CD, odds ratio (95% CI) (OR (95% CI))=2.86 ((1.34-5.88) p=0.006) and 1.39 ((0.99-1.92) p=0.054), respectively, and for UC of 2.63 ((1.33-5.26) p=0.005) and 1.28 ((0.96-1.51) p=0.093), respectively, assuming complete dominance. No association was found for BCRP or other MDR1 SNPs, or for selected MDR1 haplotypes. No effect-modification of smoking habit at the time of diagnosis was found. CONCLUSIONS An effect of the COX-2 polymorphism on both CD and UC was shown which is compatible with the presence of a recessive allele in linkage equilibrium with the SNP marker in the COX-2 gene. The polymorphism located in intron 3 of the MDR1 gene showed a weak association with CD, and a marginally suggestive association with UC.
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Associations between common variants in the MDR1 (ABCB1) gene and ulcerative colitis among North Indians. Pharmacogenet Genomics 2009; 19:77-85. [PMID: 19005421 DOI: 10.1097/fpc.0b013e32831a9abe] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES There are suggestions that the MDR1 (ABCB1) gene is associated with ulcerative colitis (UC) in Caucasians. We investigated whether common MDR1 variants were associated with UC in the genetically heterogeneous North Indian population. METHODS Confirmed cases of UC and healthy controls frequency matched for age (+/-10 years) and geographic region were studied. Three exonic (C1236T, G2677T/A, and C3435T) and one promoter (C129T) single nucleotide polymorphism (SNP) in the gene were assessed. Allelic, genotypic, and haplotypic associations were evaluated. RESULTS A total of 270 patients and 274 controls were studied. The mean age at diagnosis (+/-SD) of the patients was 38.6 (+/-12.4) years. Most patients had left-sided disease (63.3%) and steroids were administered to them (78%). All SNPs were in Hardy-Weinberg equilibrium in the controls. SNP C129T was monomorphic in the population. SNP C1236T was significantly (P=0.05) overrepresented in the UC patients. Borderline nonsignificant associations were also evident with SNP G2677A/T. Three-marker (C1236T, G2677T/A, C3435T) and two-marker (C1236T, G2677T/A) haplotype analysis revealed significant associations with UC (TTT, P=0.04; TGT, P=0.01; TT, P=0.01; CT, P=0.03). There were indications that SNPs C1236T and G2677T/A were significantly associated with earlier age of onset (<29 years) of UC and left-sided disease. Specific haplotypes comprising the three SNPs were associated with steroid response. CONCLUSION Our findings indicate that common SNPs in the MDR1 gene are associated with an overall susceptibility for UC and specific disease phenotypes in North Indians. Larger studies to replicate these findings are required.
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Wang K, Zhang H, Kugathasan S, Annese V, Bradfield JP, Russell RK, Sleiman PM, Imielinski M, Glessner J, Hou C, Wilson DC, Walters T, Kim C, Frackelton EC, Lionetti P, Barabino A, Van Limbergen J, Guthery S, Denson L, Piccoli D, Li M, Dubinsky M, Silverberg M, Griffiths A, Grant SF, Satsangi J, Baldassano R, Hakonarson H. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. Am J Hum Genet 2009; 84:399-405. [PMID: 19249008 PMCID: PMC2668006 DOI: 10.1016/j.ajhg.2009.01.026] [Citation(s) in RCA: 222] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Revised: 01/28/2009] [Accepted: 01/30/2009] [Indexed: 02/06/2023] Open
Abstract
Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 x 10(-5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently identified as genuine susceptibility genes only through meta-analysis of several GWA studies. In addition, the pathway contains other susceptibility genes for CD, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests. The observed pathway-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.
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Affiliation(s)
- Kai Wang
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Haitao Zhang
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Subra Kugathasan
- Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, GA 30322, USA
| | - Vito Annese
- Units of Gastroenterology and Endoscopy, IRCCS-CSS Hospital, 71013 San Giovanni Rotondo, Italy
| | - Jonathan P. Bradfield
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Richard K. Russell
- Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow G3 8SJ, Scotland, UK
| | - Patrick M.A. Sleiman
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Marcin Imielinski
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Joseph Glessner
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Cuiping Hou
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - David C. Wilson
- Child Life and Health, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Thomas Walters
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada
| | - Cecilia Kim
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Edward C. Frackelton
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Paolo Lionetti
- Department of Pediatrics, University Hospital Meyer, 50139 Firenze, Italy
| | - Arrigo Barabino
- Unit of Pediatrics III, Gaslini Hospital, 5-16147 Genova, Italy
| | - Johan Van Limbergen
- Gastrointestinal Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Stephen Guthery
- Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, UT 84132, USA
| | - Lee Denson
- Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - David Piccoli
- Division of Gastroenterology and Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Mingyao Li
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marla Dubinsky
- Departments of Pediatrics and Common Disease Genetics, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mark Silverberg
- Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario M5G 1X5, Canada
| | - Anne Griffiths
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada
| | - Struan F.A. Grant
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jack Satsangi
- Gastrointestinal Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Robert Baldassano
- Division of Gastroenterology and Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA
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