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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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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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Wang T, Zhou Y, Cao G. Pharmacogenetics of tamoxifen therapy in Asian populations: from genetic polymorphism to clinical outcomes. Eur J Clin Pharmacol 2021; 77:1095-1111. [PMID: 33515076 DOI: 10.1007/s00228-021-03088-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/11/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Compared with western countries, Asian breast cancer patients have unique pathological and biological characteristics. Most of them are premenopausal women with HR positive. Tamoxifen as the first-line drug for premenopausal women with HR+ is involved in multiple enzymes and transporters during metabolizing and transporting process. Variants that cause decreased or inactive gene products leading to abnormal responses in tamoxifen therapy have well been studied in western countries, whereas such information is much less reported in Asian populations. OBJECTIVE In order to elucidate the relationship between genetic variants and tamoxifen-induced individual drug reactions in different Asian populations and further identify genotypes/phenotypes with potential therapeutic significance. METHODS We reviewed the frequencies of genetic variants in major enzymes and transporter genes involved in the metabolism and transport of tamoxifen across Asian populations as well as significant correlations between genotypes/metabolic phenotypes and metabolites concentrations or BC clinical outcomes. RESULTS Significant inter-ethnic differences in allele frequencies was found among Asian populations, such as CYP2D6*4, *10, *41, CYP2C9*2, ABCB1 C3435T and SLCO1B1*5, and CYP2D6*10/*10 is the most common genotype correlated with adverse clinical outcomes. Moreover, we summarized the barriers and controversies of implementing pharmacogenetics in tamoxifen therapy and concluded that more population-specific pharmacogenetic studies are needed in the future. CONCLUSION This review revealed more systematic pharmacogenomics of genes involved in the metabolism and transport besides CYP2D6, are required to optimize the genotyping strategies and guide the personalized tamoxifen therapy in Asian populations.
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Affiliation(s)
- Tingyu Wang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden
| | - Guosheng Cao
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China.
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Sharara AI, Al Awadhi S, Alharbi O, Al Dhahab H, Mounir M, Salese L, Singh E, Sunna N, Tarcha N, Mosli M. Epidemiology, disease burden, and treatment challenges of ulcerative colitis in Africa and the Middle East. Expert Rev Gastroenterol Hepatol 2018; 12:883-897. [PMID: 30096985 DOI: 10.1080/17474124.2018.1503052] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis is an idiopathic, chronic, inflammatory bowel disorder characterized by an unpredictable course of alternating cycles of relapse and remission. Traditionally viewed as a disease of Western countries, the prevalence of ulcerative colitis is reported to be increasing in the developing world. In these regions, there is the potential to further explore the etiology of the disease, mainly through genetic studies. With this in mind, we consider available data relating to the epidemiology, clinical manifestations, and disease course of ulcerative colitis in Africa and the Middle East. Current treatment approaches in these countries are also reviewed and discussed in the context of new, small molecule, orally administered therapies. Areas covered: Available data on the epidemiology, clinical manifestations, and risk factors of ulcerative colitis in Africa and the Middle East are reviewed using a PubMed database search. Expert commentary: Epidemiologic studies from African and Middle Eastern countries suggest disease trends similar to the West, and an important health and economic burden. The management of ulcerative colitis within these developing countries is challenging, with the need to improve early diagnosis, access to healthcare, and patient education, along with facilitation of access to treatment options and improvement of medication adherence.
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Affiliation(s)
- Ala I Sharara
- a Division of Gastroenterology , American University of Beirut Medical Center , Beirut , Lebanon
| | | | - Othman Alharbi
- c Gastroenterology Division , King Khalid University Hospital, King Saud University , Riyadh , Kingdom of Saudi Arabia
| | - Hisham Al Dhahab
- d Department of Gastroenterology , Royal Hospital , Muscat , Oman
| | | | - Leonardo Salese
- f Department of Gastroenterology , Inflammation and Immunology Medical Affairs, Pfizer Inc , Collegeville , PA , USA
| | - Ena Singh
- f Department of Gastroenterology , Inflammation and Immunology Medical Affairs, Pfizer Inc , Collegeville , PA , USA
| | - Nancy Sunna
- g Department of Inflammation and Immunology , Pfizer Inc , Amman , Jordan
| | | | - Mahmoud Mosli
- h Department of Medicine , King Abdulaziz University , Jeddah , Kingdom of Saudi Arabia
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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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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 PMCID: PMC5708903 DOI: 10.17305/bjbms.2017.2172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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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Abbasi F, Soltani S, Saghazadeh A, Soltaninejad E, Rezaei A, Zare Bidoki A, Bahrami T, Amirzargar AA, Rezaei N. PTPN22 Single-Nucleotide Polymorphisms in Iranian Patients with Type 1 Diabetes Mellitus. Immunol Invest 2017; 46:409-418. [DOI: 10.1080/08820139.2017.1288239] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Cario E. P-glycoprotein multidrug transporter in inflammatory bowel diseases: More questions than answers. World J Gastroenterol 2017; 23:1513-1520. [PMID: 28321153 PMCID: PMC5340804 DOI: 10.3748/wjg.v23.i9.1513] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 01/06/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter ABCB1/MDR1 p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of ABCB1/MDR1 p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD). Recent evidence implies multiple interactions between intestinal microbiota, innate immunity and xenobiotic metabolism via p-gp. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop spontaneously chronic colitis, providing a highly valuable murine IBD model for the study of intestinal epithelial barrier function, immunoregulation, infectious co-triggers and novel therapeutic approaches. Possible associations of human ABCB1 gene polymorphisms with IBD susceptibility have been evaluated, but results are inconsistent. Future studies must focus on further elucidation of the pathophysiological relevance and immunological functions of p-gp and how its ambiguous effects could be therapeutically targeted in IBD.
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Zhao JJ, Wang D, Yao H, Sun DW, Li HY. CTLA-4 and MDR1 polymorphisms increase the risk for ulcerative colitis: A meta-analysis. World J Gastroenterol 2015; 21:10025-10040. [PMID: 26379408 PMCID: PMC4566373 DOI: 10.3748/wjg.v21.i34.10025] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 02/26/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the correlations between cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and multi-drug resistance 1 (MDR1) genes polymorphisms with ulcerative colitis (UC) risk.
METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, CBM databases, Springerlink, Wiley, EBSCO, Ovid, Wanfang database, VIP database, China National Knowledge Infrastructure, and Weipu Journal databases were exhaustively searched using combinations of keywords relating to CTLA-4, MDR1 and UC. The published studies were filtered using our stringent inclusion and exclusion criteria, the quality assessment for each eligible study was conducted using Critical Appraisal Skill Program and the resultant high-quality data from final selected studies were analyzed using Comprehensive Meta-analysis 2.0 (CMA 2.0) software. The correlations between SNPs of CTLA-4 gene, MDR1 gene and the risk of UC were evaluated by OR at 95%CI. Z test was carried out to evaluate the significance of overall effect values. Cochran’s Q-statistic and I2 tests were applied to quantify heterogeneity among studies. Funnel plots, classic fail-safe N and Egger’s linear regression test were inspected for indication of publication bias.
RESULTS: A total of 107 studies were initially retrieved and 12 studies were eventually selected for meta-analysis. These 12 case-control studies involved 1860 UC patients and 2663 healthy controls. Our major result revealed that single nucleotide polymorphisms (SNPs) of CTLA-4 gene rs3087243 G > A and rs231775 G > A may increase the risk of UC (rs3087243 G > A: allele model: OR = 1.365, 95%CI: 1.023-1.822, P = 0.035; dominant model: OR = 1.569, 95%CI: 1.269-1.940, P < 0.001; rs231775 G > A: allele model: OR = 1.583, 95%CI: = 1.306-1.918, P < 0.001; dominant model: OR = 1.805, 95%CI: 1.393-2.340, P < 0.001). In addition, based on our result, SNPs of MDR1 gene rs1045642 C > T might also confer a significant increases for the risk of UC (allele model: OR = 1.389, 95%CI: 1.214-1.590, P < 0.001; dominant model: OR = 1.518, 95%CI: 1.222-1.886, P < 0.001).
CONCLUSION: CTLA-4 gene rs3087243 G > A and rs231775 G > A, and MDR1 gene rs1045642 C > T might confer an increase for UC risk.
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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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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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Chiurillo MA. Can the prevalence of symptoms in patients with inflammatory bowel disease be predicted by the analysis of multidrug resistance gene 1 polymorphisms? Saudi J Gastroenterol 2013; 19:139-40. [PMID: 23828741 PMCID: PMC3745653 DOI: 10.4103/1319-3767.114502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Miguel Angel Chiurillo
- Department of Functional Sciences, Molecular Genetic Laboratory Dr. Jorge Yunis-Turbay, School of Medicine, Lisandro Alvarado Central Western University, Barquisimeto, Venezuela E-mail:
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Al-Mohizea AM, Alkharfy KM, Bagulb KM, Alghamdi AM, Al-Jenoobi FI, Al-Muhsen S, Halwani R, Parvez MK, Al-Dosari MS. Genetic variability and haplotype profile of MDR1 in Saudi Arabian males. Mol Biol Rep 2012; 39:10293-10301. [PMID: 23053935 DOI: 10.1007/s11033-012-1906-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 09/30/2012] [Indexed: 01/11/2023]
Abstract
Polymorphisms in multidrug resistance (MDR1) gene play an important role in influencing the pharmacological action and toxicity profile of a large number of therapeutic agents, and in human susceptibility to various diseases. Because of genotypic variability, several studies were directed toward determination of the frequencies of MDR1 polymorphisms and/or haplotypes in different ethnic populations. In this study, we determined the frequencies of the most common three polymorphisms in the MDR1 gene (i.e., C1236T, G2677T, and C3435T) in Saudi Arabians and their haplotypes. Our results showed that the frequencies of 1236T, 2677T, and 3435T were 43.7 %, 40.2 %, and 42.2 %, respectively. In addition, the frequencies of the most common MDR1 haplotypes, C-G-C and T-T-T, were correspondent to 48.8 and 35.5 %. Furthermore, we identified moderate to strong linkage disequilibrium between the loci of these single nucleotide polymorphisms in the studied subjects. These identified frequencies in Saudi Arabians are different from that reported in the other ethnic groups.
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Affiliation(s)
- Abdullah M Al-Mohizea
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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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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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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Abstract
Ulcerative colitis (UC) is a chronic intestinal inflammatory disease whose etiology is still unknown. It is widely believed that UC is a kind of non-specific inflammatory disease which is caused by environmental factors and autoimmune disorders in people who carry susceptibility genes. Epidemiologic data, such as familial aggregation, twin studies, and racial/ethnic differences in disease prevalence, indicate that there are genetic contributions to UC pathogenesis. In this article, we will review the recent progress in research of genes associated with susceptibility to UC.
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Mhaidat NM, Alshogran OY, Khabour OF, Alzoubi KH, Matalka II, Haddadin WJ, Mahasneh IO, Aldaher AN. Multi-drug resistance 1 genetic polymorphism and prediction of chemotherapy response in Hodgkin's Lymphoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:68. [PMID: 21762523 PMCID: PMC3154152 DOI: 10.1186/1756-9966-30-68] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2011] [Accepted: 07/16/2011] [Indexed: 11/10/2022]
Abstract
Background The human multi-drug resistance gene (MDR1), which encodes the major trans-membrane transporter P-glycoprotein (P-gp), was found to be associated with susceptibility to cancer and response to chemotherapy. The C3435T Polymorphism of MDR1 gene was correlated with expression levels and functions of P-gp. Here, we studied the association between MDR1 C3435T polymorphism and susceptibility to Hodgkin lymphoma (HL) and patient's response to ABVD chemotherapy regimen. Methods a total of 130 paraffin embedded tissue samples collected from HL patients were analyzed to identify the C3435T polymorphism. As a control group, 120 healthy subjects were enrolled in the study. The C3435T Polymorphism was genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism. Results these studies revealed that the frequency of T allele was significantly higher in HL patients compared to the controls (P < 0.05). In addition, the frequency of CT and TT genotypes were also significantly higher in HL patients compared to the controls (P < 0.05). No association between C3435T polymorphism and response to ABVD was detected among HL patients (P > 0.05). Conclusions these results suggest that MDR1 C3435T polymorphism might play a role in HL occurrence; however this polymorphism is not correlated with the clinical response to ABVD.
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Affiliation(s)
- Nizar M Mhaidat
- Clinical Pharmacy Department, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
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Abstract
PURPOSE The NOD2 gene is known to have a strong association with Crohn's disease, but different trends were reported in occurrence of NOD2 variants in distinct ethnicities. The aim of this study was to assess all exonic sequences of the NOD2 gene in Iranian Crohn's disease patients and healthy controls to identify any existing variation and evaluate their association with Crohn's disease. METHODS A total of 90 non-related Crohn's disease patients and 120 sex- and age-matched healthy controls of Iranian origin were enrolled in this study. The participants were referred to a tertiary center in a 2-year period (2006-2008). The exonic regions of the NOD2 gene were amplified by polymerase chain reaction and evaluated by direct sequencing. RESULTS A total of 21 sequence variations were identified among all exonic regions of the NOD2 gene, of which eight had an allele frequency of more than 5%. Eight new mutations (one in exon 2 and seven in exon 4) were observed. The three main variants (R702W, G908R, and 1007fs) showed allele frequencies of 13.3%, 2.2%, and 1.7%, respectively. Three new variations (P371T, A794P, and Q908H) and R702W mutation were significantly more frequent in Crohn's disease patients compared to controls. CONCLUSIONS Eight novel mutations were identified in the NOD2 exons, but the pathophysiological importance of these variants remains unclear. Iranian patients with their different genetic reservoirs may demonstrate some novel characteristics for disease susceptibility.
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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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Errasti-Murugarren E, Pastor-Anglada M. Drug transporter pharmacogenetics in nucleoside-based therapies. Pharmacogenomics 2010; 11:809-41. [PMID: 20504255 DOI: 10.2217/pgs.10.70] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
This article focuses on the different types of transporter proteins that have been implicated in the influx and efflux of nucleoside-derived drugs currently used in the treatment of cancer, viral infections (i.e., AIDS) and other conditions, including autoimmune and inflammatory diseases. Genetic variations in nucleoside-derived drug transporter proteins encoded by the gene families SLC15, SLC22, SLC28, SLC29, ABCB, ABCC and ABCG will be specifically considered. Variants known to affect biological function are summarized, with a particular emphasis on those for which clinical correlations have already been established. Given that relatively little is known regarding the genetic variability of the players involved in determining nucleoside-derived drug bioavailability, it is anticipated that major challenges will be faced in this area of research.
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Affiliation(s)
- Ekaitz Errasti-Murugarren
- The Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, Diagonal 645, 08028 Barcelona, Spain
- Center for Biomedical Research Network in the Subject Area of Liver and Digestive Diseases (CIBERehd), Barcelona 08071, Spain
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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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Tatari F, Salek R, Mosaffa F, Khedri A, Behravan J. Association of C3435T single-nucleotide polymorphism of MDR1 gene with breast cancer in an Iranian population. DNA Cell Biol 2009; 28:259-63. [PMID: 19388849 DOI: 10.1089/dna.2008.0826] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The human multidrug resistance gene 1 (MDR1) encodes a plasma membrane, P-glycoprotein (Pgp), which functions as the transmembrane efflux pump for various structurally unrelated anticancer agents and toxins. Polymorphisms in the MDR1 gene may have an impact on the expression and function of Pgp, thereby influencing the susceptibility to various diseases, including cancer. Recently, a silent C3435T polymorphism in exon 26 of MDR1 has been reported to be associated with decreased expression of Pgp in TT genotype carriers and thus it may alter the physiological protective role of Pgp and influence disease risk. To evaluate the association of this polymorphism with breast cancer, 106 patients with breast cancer and 77 healthy controls were enrolled in this study. They were visited at two centers during a 1-year period (2006-2007). Data about the risk factors of breast cancer were collected using questionnaires. DNA of the whole-blood sample was extracted, and the polymorphic fragment was amplified by polymerase chain reaction using specific primers. The C3435T polymorphism was detected by the restriction fragment length polymorphism method. There were no significant differences in genotype (p = 0.744) and allele (p = 0.590) frequencies between patients and control subjects. Moreover, distribution of the breast cancer patients' risk factors was not different among CC, CT, and TT genotypes. Our results suggest that C3435T MDR1 polymorphism was not associated with the susceptibility to breast cancer in the population studied.
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Affiliation(s)
- Farnoosh Tatari
- Biotechnology Research Center, Imam Reza(A) and Omid Hospitals, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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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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Naderi N, Farnood A, Habibi M, Derakhshan F, Balaii H, Motahari Z, Agah MR, Firouzi F, Rad MG, Aghazadeh R, Zojaji H, Zali MR. Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease. J Gastroenterol Hepatol 2008; 23:1816-22. [PMID: 18752562 DOI: 10.1111/j.1440-1746.2008.05525.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The vitamin D receptor (VDR) gene maps to a region on chromosome 12 shown to be linked to inflammatory bowel disease (IBD). Many studies have recognized the relation of VDR gene polymorphisms with inflammatory and autoimmune disorders. Determining the frequency of these polymorphisms and their possible relation with IBD can improve understandings about the genetic background of these diseases. The objective of this study was to assess the association of VDR gene polymorphisms (Apa I, Taq I, Bsm I, Fok I) with IBD in Iran. METHODS In this case control designed study 150 patients with ulcerative colitis, 80 patients with Crohn's disease and 150 Age and Sex matched healthy controls from Iranian origin were enrolled. These patients were referred to a tertiary center during a two-year period (2004-2006). Assessment of VDR gene polymorphisms was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The genotype-phenotype association for these polymorphisms was analyzed. RESULTS Only the frequency of the Fok I polymorphism was significantly higher in ulcerative colitis and Crohn's groups. The frequency of the polymorphic allele f was higher in ulcerative colitis and Crohn's patients comparing with controls (P = 0.011 and P < 0.001, respectively). The f/f genotype was also significantly more frequent (P < 0.001), while the F/F genotype was less presented in Crohn's patients compared to controls (P < 0.001). No genotype-phenotype association was observed with any mutations. CONCLUSIONS This study suggests a probable association of the Fok I polymorphism in VDR receptor gene and Crohn's susceptibility in Iranian population.
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Affiliation(s)
- Nosratollah Naderi
- Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University, MC, Tehran, Iran
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Vicente J, Sinues B, Fanlo A, Vasquez P, Medina JC, Martinez-Jarreta B. Polymorphism C3435T of the MDR1 gene in Central Americans and Spaniards. Mol Biol Rep 2007; 35:473-8. [PMID: 17577681 DOI: 10.1007/s11033-007-9109-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2007] [Accepted: 05/31/2007] [Indexed: 01/11/2023]
Abstract
The human multidrug resistance gene (MDR1) encodes for P-glycoprotein (P-gp) which is a transmembrane transporter protein that acts as an efflux pump for a number of lypophilic compounds. It plays a protective role for cells against DNA damage. The wobble C3435T polymorphism at exon 26 has been associated with different expression levels and activity. Differences in allele frequency of the C3435T polymorphism have been demonstrated between distinct ethnic groups. In our study we examined these polymorphisms in 433 healthy individuals. From these, 229 were Central American mestizos from Nicaragua (n = 117) and El Salvador (n = 112) to be compared with a group of 204 North Spaniards, with the aim of detecting potential genotypic differences between these populations. The genotypes were determined by PCR-RFLP. The frequencies of the C allele were very similar among Central Americans (0.53) and Spaniards (0.52), which is consistent with the ethnic origin of Central American individuals (Amerindians and European Caucasians). In comparison to other previously studied populations, the C allele frequency in Central Americans was significantly lower than that found in African populations and higher than that observed in the Indian and Southwest Asian populations. These data may be relevant for dose recommendation of P-gp substrate drugs and also for studies of allele disease association in the Central American population.
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Affiliation(s)
- J Vicente
- Department of Pharmacology, Medicine School, University of Zaragoza, Domingo Miral s/n, Zaragoza, Spain
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