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Jara-Prado A, Guerrero-Camacho JL, Ángeles-López QD, Ochoa-Morales A, Dávila-Ortiz de Montellano DJ, Ramírez-García MÁ, Breda-Yepes M, Durón RM, Delgado-Escueta AV, Barrios-González DA, Martínez-Juárez IE. Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy. Neurol Sci 2024; 45:1635-1643. [PMID: 37875597 DOI: 10.1007/s10072-023-07124-w] [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: 06/15/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023]
Abstract
Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.
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Affiliation(s)
- Aurelio Jara-Prado
- Genetics Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | | | | | - Adriana Ochoa-Morales
- Genetics Department, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
| | | | | | - Michelle Breda-Yepes
- National Institute of Neurology and Neurosurgery, Epilepsy Clinic, Mexico City, Mexico
| | - Reyna M Durón
- Universidad Tecnológica Centroamericana (UNITEC), Tegucigalpa, Honduras
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Caliendo G, D'Elia G, Makker J, Passariello L, Albanese L, Molinari AM, Vietri MT. Biological, genetic and epigenetic markers in ulcerative colitis. Adv Med Sci 2023; 68:386-395. [PMID: 37813048 DOI: 10.1016/j.advms.2023.09.010] [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: 11/17/2022] [Revised: 04/15/2023] [Accepted: 09/18/2023] [Indexed: 10/11/2023]
Abstract
In this review, we have summarized the existing knowledge of ulcerative colitis (UC) markers based on current literature, specifically, the roles of potential new biomarkers, such as circulating, fecal, genetic, and epigenetic alterations, in UC onset, disease activity, and in therapy response. UC is a complex multifactorial inflammatory disease. There are many invasive and non-invasive diagnostic methods in UC, including several laboratory markers which are employed in diagnosis and disease assessment; however, colonoscopy remains the most widely used method. Common laboratory abnormalities currently used in the clinical practice include inflammation-induced alterations, serum autoantibodies, and antibodies against bacterial antigens. Other new serum and fecal biomarkers are supportive in diagnosis and monitoring disease activity and therapy response; and potential salivary markers are currently being evaluated as well. Several UC-related genetic and epigenetic alterations are implied in its pathogenesis and therapeutic response. Moreover, the use of artificial intelligence in the integration of laboratory biomarkers and big data could potentially be useful in clinical translation and precision medicine in UC management.
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Affiliation(s)
- Gemma Caliendo
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanna D'Elia
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Jasmine Makker
- Department of GKT School of Medical Education, King's College London, London, UK
| | - Luana Passariello
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luisa Albanese
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Maria Molinari
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Teresa Vietri
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
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Investigating Key Targets of Dajianzhong Decoction for Treating Crohn’s Disease Using Weighted Gene Co-Expression Network. Processes (Basel) 2022. [DOI: 10.3390/pr11010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background: Crohn’s disease (CD) is an inflammatory bowel disease, cases of which have substantially increased in recent years. The classical formula Dajianzhong decoction (DD, Japanese: Daikenchuto) is often used to treat CD, but few studies have evaluated related therapeutic mechanisms. In this study, we investigated the potential targets and mechanisms of DD used for treating CD at the molecular level through the weighted gene co-expression network. Methods: The main chemical components of the three DD herbs (Zanthoxylum bungeanum Maxim., Zingiber officinale (Willd.) Rosc., and Ginseng Radix et Rhizoma) were searched for using the HERB database. The targets for each component were identified using the SwissTargetPrediction and HERB databases, whereas the disease targets for CD were retrieved from the GeneCards and DisGeNET databases. The functional enrichment analysis was performed on the common targets of DD and CD. High-throughput sequencing data for CD patients were retrieved from the Gene Expression Omnibus database, and WGCNA was performed to identify the key targets. The association between the key targets and DD ingredients was verified using molecular docking. Results: By analyzing the interaction targets between DD and CD, 196 overlapping genes were identified. The enrichment results indicated that the PI3K-AKT, TNF, MAPK, and IL-17 signaling pathways influenced the mechanism of action of DD in counteracting CD. Combined with WGCNA, four differentially expressed genes (SLC6A4, NOS2, SHBG, and ABCB1) and their corresponding 24 compounds were closely related to the occurrence of CD. Conclusions: By integrating gene co-expression network analysis, this study preliminarily reveals the internal molecular mechanism of DD in treating CD from a systematic perspective, validated by molecular docking. However, these findings require further validation.
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Guerrero Camacho JL, Corona Vázquez T, Flores Rivera JJ, Ochoa Morales A, Martínez Ruano L, Torres Ramírez de Arellano I, Dávila Ortiz de Montellano DJ, Jara Prado A. ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients. NEUROLOGÍA (ENGLISH EDITION) 2022; 38:65-74. [PMID: 35256320 DOI: 10.1016/j.nrleng.2020.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/05/2020] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P = .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P = .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P = .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P = .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P = .001). TTTTTT carriers presented the earliest age of onset (23.0 ± 7.7 years, vs 31.6 ± 10.7; P = .0001). CONCLUSIONS The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
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Affiliation(s)
- J L Guerrero Camacho
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - T Corona Vázquez
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - J J Flores Rivera
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - A Ochoa Morales
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - L Martínez Ruano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - I Torres Ramírez de Arellano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - D J Dávila Ortiz de Montellano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - A Jara Prado
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico.
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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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Guerrero Camacho JL, Corona Vázquez T, Flores Rivera JJ, Ochoa Morales A, Martínez Ruano L, Torres Ramírez de Arellano I, Dávila Ortiz de Montellano DJ, Jara Prado A. ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients. Neurologia 2020; 38:S0213-4853(20)30216-4. [PMID: 32912743 DOI: 10.1016/j.nrl.2020.05.013] [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: 01/30/2020] [Revised: 04/28/2020] [Accepted: 05/05/2020] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI: 1.12-2.86; P=.015), as were the genotypes GG2677 (OR: 2.72; 95% CI: 1.11-6.68; P=.025) and CC3435 (OR: 1.82; 95% CI: 1.15-2.90; P=.010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P=.010), and the CAT haplotype (OR: 0.21; 95% CI: 0.05-0.66; P=.001). TTTTTT carriers presented the earliest age of onset (23.0±7.7 years, vs. 31.6±10.7; P=.0001). CONCLUSIONS The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
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Affiliation(s)
- J L Guerrero Camacho
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - T Corona Vázquez
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - J J Flores Rivera
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - A Ochoa Morales
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - L Martínez Ruano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - I Torres Ramírez de Arellano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - D J Dávila Ortiz de Montellano
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
| | - A Jara Prado
- Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México.
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Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients. Sci Rep 2020; 10:11725. [PMID: 32678214 PMCID: PMC7366697 DOI: 10.1038/s41598-020-68686-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G > T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G > T, MDR1 3435C > T and PXR -25385C > T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR = 3.34, 95% CI = 1.58–7.05, p = 0.002) and earlier progression to surgery (hazard ratio, HR = 3.00, 95% CI = 1.86–4.83, p < 0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22–52.38, p < 0.0001) and early progression to surgery (HR = 6.28, 95% CI = 3.62–10.90, p < 0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p < 0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.
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Zhu Y, Jiang H, Chen Z, Lu B, Li J, Shen X. Genetic association between IL23R rs11209026 and rs10889677 polymorphisms and risk of Crohn’s disease and ulcerative colitis: evidence from 41 studies. Inflamm Res 2019; 69:87-103. [DOI: 10.1007/s00011-019-01296-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/11/2019] [Accepted: 10/31/2019] [Indexed: 01/30/2023] Open
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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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Amir Shaghaghi M, Zhouyao H, Tu H, El-Gabalawy H, Crow GH, Levine M, Bernstein CN, Eck P. The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease. Am J Clin Nutr 2017; 106:1508-1513. [PMID: 28971850 PMCID: PMC5698836 DOI: 10.3945/ajcn.116.147603] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 09/01/2017] [Indexed: 01/16/2023] Open
Abstract
Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD.Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD.Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene.Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1.95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively).Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.
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Affiliation(s)
| | | | - Hongbin Tu
- Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD
| | | | | | - Mark Levine
- Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD
| | - Charles N Bernstein
- Internal Medicine, and,IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Canada; and
| | - Peter Eck
- Departments of Human Nutritional Sciences,
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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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Barańska M, Rychlik-Sych M, Skrętkowicz J, Dudarewicz M, Dziankowska-Bartkowiak B, Owczarek J, Waszczykowska E. Genotype and haplotype analysis of ABCB1 at 1236, 2677 and 3435 among systemic sclerosis patients. Autoimmunity 2017; 50:277-282. [PMID: 28534442 DOI: 10.1080/08916934.2017.1329421] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Systemic sclerosis (SSc) belongs to the group of systemic diseases of the connective tissue, which are characterized by a chronic autoimmune inflammatory process. P-glycoprotein, initially associated with the drug resistance in patients with cancer, becomes more and more often a subject of considerations in terms of its significance in the development of illnesses, including autoimmune diseases. The aim of the study was an attempt to answer the question whether there was a relationship between ABCB1 polymorphisms and morbidity of systemic sclerosis in a Polish population. The study was carried out in 61 patients with SSc and 100 healthy volunteers. Determination of polymorphisms C1236T and C3435T in ABCB1 was carried out with the PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) method. The G2677T/A ABCB1 polymorphism was analysed with the allele-specific PCR method. No statistically significant differences were observed in the frequencies of ABCB1 genotypes and alleles between SSc patients and the control group. It was observed that haplotype 1236 C-2677 G-3435 T occurred in the group of patients with SSc statistically more frequently than in the group of healthy volunteers (25% vs. 15%; p = .032). Carriers of the haplotype demonstrated almost a twofold greater risk of SSc (OR = 1.85; p = .032). No statistically significant correlations for the other nine haplotypes were found. Presented results concerning the relationship of ABCB1 polymorphisms with susceptibility to systemic sclerosis are the first ones that were obtained in a Polish population. They imply that single nucleotide polymorphisms do not affect the risk for SSc, but the 1236 C-2677 G-3435 T haplotype might increase this risk.
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Affiliation(s)
- Małgorzata Barańska
- a Department of Pharmacogenetics , Chair of Biopharmacy, Medical University of Lodz , Łódź , Poland
| | - Mariola Rychlik-Sych
- a Department of Pharmacogenetics , Chair of Biopharmacy, Medical University of Lodz , Łódź , Poland
| | - Jadwiga Skrętkowicz
- a Department of Pharmacogenetics , Chair of Biopharmacy, Medical University of Lodz , Łódź , Poland
| | - Michał Dudarewicz
- a Department of Pharmacogenetics , Chair of Biopharmacy, Medical University of Lodz , Łódź , Poland
| | - Bożena Dziankowska-Bartkowiak
- b Department of Dermatology and Venereology, Chair of Dermatology and Venereology , Medical University of Lodz , Łódź, Poland
| | - Jacek Owczarek
- a Department of Pharmacogenetics , Chair of Biopharmacy, Medical University of Lodz , Łódź , Poland
| | - Elżbieta Waszczykowska
- b Department of Dermatology and Venereology, Chair of Dermatology and Venereology , Medical University of Lodz , Łódź, Poland
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13
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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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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: 15] [Impact Index Per Article: 1.5] [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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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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16
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Bonyadi M, Gholizadeh M, Soltan-Ali M. MDR1 C3435T polymorphism associated with the development of clinical features in Behçet's disease in Iranian Azeri Turkish patients. Int J Dermatol 2014; 53:1235-40. [PMID: 24898446 DOI: 10.1111/ijd.12540] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Behçet's disease (BD) is a systemic vasculitis of unknown cause with a higher prevalence along the ancient Silk Road. Behçet's occasional familial aggregation and its close association with genes of major histocompatibility complexes justify that genetic factors play an important role in the development of the disease. In this study, we evaluated the association of multidrug resistance (MDR1) C3435T polymorphism with the severity of BD. METHOD We investigated the distribution of MDR1 C3435T polymorphism in 69 patients from the Iranian Azeri Turks group with BD and 92 ethnically sex-matched healthy controls, via the polymerase chain reaction-restriction fragment length polymorphism technique. RESULT Although there was no significant association of MDR1 C3435T polymorphism between two groups of patients and healthy controls, our data showed a substantial association of CC genotype with the development of several clinical features, including erythema nodosum (P = 0.001, OR = 2.686, 95%), pseudofolliculitis (P = 0.002, OR = 2.812, 95%), and skin lesions (P = 0.040, OR = 1.934, 95%). CONCLUSION These results suggest that CC genotype is a risk factor for the development of some clinical features of BD in patients from the Iranian Azeri Turk ethnic group.
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Affiliation(s)
- Mortaza Bonyadi
- Center of Excellence for Biodiversity, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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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; 69:327-334. [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] [Revised: 09/19/2013] [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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Kim HJ, Um JY, Kim YK. Association of a multidrug resistance 1 gene polymorphism and colorectal cancer in the Korean population. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s13596-013-0136-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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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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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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22
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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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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2012; 18:105-18. [PMID: 22253516 PMCID: PMC3257437 DOI: 10.3748/wjg.v18.i2.105] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 04/25/2011] [Accepted: 05/02/2011] [Indexed: 02/06/2023] Open
Abstract
Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2011; 17:5246-59. [PMID: 22219593 PMCID: PMC3247688 DOI: 10.3748/wjg.v17.i48.5246] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Considering the epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have so far been related to the diagnosis of Crohn's disease. These genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the strongest and most replicated associations with Crohn's disease have been demonstrated with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in the prognosis of Crohn's disease and many attempts have been made for classification of genetic profiles in Crohn's disease. CARD15 seems to be not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding of Crohn's disease genetics is of value, but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Krupoves A, Mack D, Seidman E, Deslandres C, Amre D. Associations between variants in the ABCB1 (MDR1) gene and corticosteroid dependence in children with Crohn's disease. Inflamm Bowel Dis 2011; 17:2308-17. [PMID: 21987299 DOI: 10.1002/ibd.21608] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Accepted: 11/10/2010] [Indexed: 01/11/2023]
Abstract
BACKGROUND Corticosteroids (CS) effectively induce remission in patients with moderate to severe Crohn's disease (CD). However, CS dependence in children is a significant clinical problem associated with numerous side effects. Identification of molecular markers of CS dependence is of paramount importance. The ABCB1 gene codes for P-glycoprotein, a transporter involved in the metabolism of CS. We examined whether DNA variation in the ABCB1 gene was associated with CS dependency in children with CD. METHODS A retrospective study was carried out in two Canadian tertiary pediatric gastroenterology centers. Clinical information was abstracted from medical charts of CD patients (N = 260) diagnosed with CD prior to age 18 and administered a first course of CS during the 1 year since diagnosis. Patients were classified as CS-dependent if they relapsed during drug tapering or after the end of therapy. DNA was extracted from blood or saliva. Thirteen tagging single nucleotide polymorphisms (tag-SNPs) and a synonymous variation (C3435T) in the ABCB1 gene were genotyped. Allelic, genotype, and haplotype associations were examined using logistic regression and Haploview. RESULTS Tag-SNP rs2032583 was statistically significantly associated with CS dependency. The rare C allele of this SNP (odds ratio [OR] = 0.56, 95% confidence interval [CI]: 0.34-0.95, P = 0.029) and heterozygous genotype TC (OR = 0.52, 95% CI: 0.28-0.95, P = 0.035) conferred protection from CS dependency. A three-marker haplotype was significantly associated with CS dependence (multiple comparison corrected P-value = 0.004). CONCLUSIONS Our results suggest that the ABCB1 gene may be associated with CS dependence in pediatric CD patients.
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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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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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Abstract
PURPOSE The aim of this study was to determine the significance of three most common single-nucleotide polymorphisms (SNPs) of ABCB1 gene in the development of colorectal cancer and to estimate the influence of these SNPs to surviving patients' treatment combination adjuvant therapy 5-fluorouracil/leucovorin. Haplotype structure of ABCB1 was analysed, and degree of linkage disequilibrium (LD) between SNPs of ABCB1 was estimated. MATERIALS AND METHODS Tumour specimens of 95 patients with colorectal cancer and blood samples of 95 healthy cases were studied. Genotyping of ABCB1 gene was performed by automated sequencing or polymerase chain reaction-restriction fragment length polymorphism method. Comparison of frequencies of alleles/genotypes/haplotypes between the studied group (colorectal cancer samples) and the control group (blood samples) were analysed. These results were correlated with the surviving patients after treatment of adjuvant chemotherapy. RESULTS Significant differences in ABCB1 (1236C>T) (p = 0.00043) and ABCB1 (2677G>T/A) (p = 0.04) genotype distribution and T(1236) allele distribution (CT(1236) or TT(1236) vs CC(1236); p = 0.0499, OR = 0.55, Fi-Yule coefficient = 0.14) were found. A strong LD between ABCB1 (1236C>T) and ABCB1 (2677G>T/A) SNPs (D' = 0.621, r (2) = 0.318) was detected. All SNPs were located in one haplotype block. There were significant differences in haplotype distributions between colorectal cancer patients and healthy population (p = 0.03). Significant differences in survival probability of colorectal cancer patients' treatment chemotherapy according to allele of ABCB1 (3435C>T) was observed. Survival probability of patients with wild-type C(3435) allele were higher than among patients without this allele (p = 0.04572). CONCLUSIONS These results suggested that three studied SNPs of ABCB1 were located in one haplotype block. Differences in ABCB1 (1236C>T) and ABCB1 (2677G>T/A) genotypes and T(1236) allele distribution between investigated populations indicate significant impact of these SNPs on risk of development of colorectal cancer. Polymorphism ABCB1 (3435C>T) may be a prediction marker of cancer chemotherapy effectiveness. Differences in haplotype distributions between colorectal cancer patients and healthy population suggested that other potential SNPs, especially in regulatory region of ABCB1 gene, may influence P-glycoprotein expression and function.
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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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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: 27] [Impact Index Per Article: 1.7] [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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Neuhausen SL, Steele L, Ryan S, Mousavi M, Pinto M, Osann KE, Flodman P, Zone JJ. Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. J Autoimmun 2008; 31:160-5. [PMID: 18692362 PMCID: PMC2630860 DOI: 10.1016/j.jaut.2008.06.001] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Revised: 06/16/2008] [Accepted: 06/30/2008] [Indexed: 12/13/2022]
Abstract
The occurrence of other autoimmune diseases in celiac disease families has not been previously reported in a North American population. We investigated the familial aggregation of rheumatoid arthritis (RA), juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), hypothyroidism, insulin dependent diabetes mellitus (IDDM), and alopecia areata (AA) among individuals in families with celiac disease (CD). Family history information, obtained from questionnaires from the University of California Irvine Celiac Disease study, was reviewed for reports of RA, JRA/JIA, hypothyroidism, IDDM, and AA in celiac disease cases and their first-degree relatives. Reports of disease were compared with prevalence data from the literature and analyzed by calculating the standardized ratio (SR) with 95% confidence limits. We analyzed: (1) subjects with confirmed celiac disease or dermatitis herpetiformis (205 probands and 203 affected first-degree relatives) and (2) first-degree relatives of celiac disease cases (n=1272). We found a significantly increased number of cases, relative to the expected number, of IDDM in both groups and hypothyroidism among subjects with celiac disease. JRA/JIA was increased among first-degree relatives of celiacs. These results indicate that the presence of IDDM within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general.
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Affiliation(s)
- Susan L Neuhausen
- Department of Epidemiology, University of California Irvine, 224 Irvine Hall, Irvine, CA 92697-7550, USA.
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Abstract
The considerable interindividual differences in efficacy and side effects of commonly used medications in Crohn’s disease are partly owing to genetic polymorphisms. Many genetic variants have been studied in genes possibly involved in the metabolism or mechanism of action of therapeutic agents such as glucocorticosteroids, azathioprine/6-mercaptopurine, methotrexate, calcineurin inhibitors or anti-TNF agents. However, the only test translated into clinical practice is thiopurine S-methyltransferase (TPMT) genotyping for hematological toxicity of thiopurine treatment. To date, there are no other meaningful applications for pharmacogenomics in clinical practice of Crohn’s disease. In the future, designed therapeutic trials should possibly permit the development of predictive models including genotypic markers, such as that proposed for the clinical outcome after infliximab therapy, which includes an apoptotic pharmacogenetic index. The recent identification of new susceptibility genes provides additional candidate markers that have possible effects on the outcomes of therapies, and prioritizes new therapeutic targets, such as the IL-23 pathway. Futher innovative approaches might be relevant for the pharmacogenetic investigation of gene variants implied in innate immune pattern recognition and autophagy.
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Affiliation(s)
- Helga-Paula Török
- University of Munich, Department of Internal Medicine II, Campus Großhadern, Marchioninistr. 15, D-81377 Munich, Germany
| | - Burkhard Göke
- University of Munich, Department of Internal Medicine II, Campus Großhadern, Marchioninistr. 15, D-81377 Munich, Germany
| | - Astrid Konrad
- University of Munich, Department of Internal Medicine II, Campus Großhadern, Marchioninistr. 15, D-81377 Munich, Germany
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Abstract
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.
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Hüebner C, Petermann I, Browning BL, Shelling AN, Ferguson LR. Triallelic single nucleotide polymorphisms and genotyping error in genetic epidemiology studies: MDR1 (ABCB1) G2677/T/A as an example. Cancer Epidemiol Biomarkers Prev 2007; 16:1185-92. [PMID: 17548683 DOI: 10.1158/1055-9965.epi-06-0759] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Accurate measurement of allele frequencies between population groups with differing sensitivities to disease is fundamental to genetic epidemiology. Genotyping errors can markedly influence the biological conclusions of a study. This issue may be especially important now there is increasing recognition of triallelic single nucleotide polymorphisms (SNPs) in the genome and their possible role in diseases like inflammatory bowel disease. For example, the MDR1 (ABCB1) SNP G2677/T/A was, like many other triallelic SNPs, originally described as diallelic. Here, we report a comprehensive analyses of estimated allele frequencies of this SNP in a set of 73 human DNA samples, comparing six commonly used genotyping methods (Applied Biosystems Taqman, Roche LightCycler melting analysis, allelic discrimination PCR, DNA sequencing, Sequenom, and RFLP) from the angle of their error potential. Only Sequenom and DNA sequencing provided accurate measurements, if we had not had prior knowledge of the triallelic nature of this SNP. The other tested methods (with the exception of LightCycler) failed to show any indication of the presence of the rare third A- allele in a diallelic assay. Although most of the errors were due to the inability to detect the third allele, all methods except Sequenom and sequencing produced errors for the detection of the two common alleles G and T (LightCycler, 6 errors; PCR, 4 errors; RFLP, 2 errors; Taqman, 1 error). There is considerable variability in the reported frequencies of the different alleles of the MDR1 G2677/T/A SNP, and the role of this SNP in the etiology of inflammatory bowel disease has been controversial. Our data emphasize the importance of choosing the appropriate method for SNP detection and lead us to suggest that part of the previously reported variation may reflect artifacts associated with the different genotyping methodologies used. The failure to recognize the triallic nature of a SNP may lead to underestimations of real genetic associations.
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Affiliation(s)
- Claudia Hüebner
- Discipline of Nutrition, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Furuta T, Sugimoto M, Shirai N, Matsushita F, Nakajima H, Kumagai J, Senoo K, Kodaira C, Nishino M, Yamade M, Ikuma M, Watanabe H, Umemura K, Ishizaki T, Hishida A. Effect of MDR1 C3435T polymorphism on cure rates of Helicobacter pylori infection by triple therapy with lansoprazole, amoxicillin and clarithromycin in relation to CYP 2C19 genotypes and 23S rRNA genotypes of H. pylori. Aliment Pharmacol Ther 2007; 26:693-703. [PMID: 17697203 DOI: 10.1111/j.1365-2036.2007.03408.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Polymorphism in MDR1 is associated with variation in the plasma level of a proton pump inhibitor. AIM To investigate whether MDR1 polymorphism is associated with eradication rates of Helicobacter pylori by a triple therapy with lansoprazole, amoxicillin and clarithromycin in relation to CYP2C19 genotype status and bacterial susceptibility to clarithromycin. METHODS A total of 313 patients infected with H. pylori completed the treatment with lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week. MDR1 C3435T polymorphism and CYP2C19 genotypes of patients and sensitivity of H. pylori to clarithromycin were determined. RESULTS Logistic regression analysis revealed that the MDR1 polymorphism as well as CYP2C19 genotypes of patients and clarithromycin-resistance of H. pylori were significantly associated with successful eradication. Eradication rates for H. pylori were 82% (83/101: 95% CI = 73-89), 81% (112/139: CI = 73-87), and 67% (44/73: CI = 48-72) in patients with the MDR1 3435 C/C, C/T and T/T genotype, respectively (P = 0.001). CONCLUSIONS Polymorphism of MDR1 is one of the determinants of successful eradication of H. pylori by the triple therapy with lansoprazole, amoxicillin and clarithromycin, together with CYP2C19 genotype and bacterial susceptibility to clarithromycin.
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Affiliation(s)
- T Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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Petrova DT, Nedeva P, Maslyankov S, Toshev S, Yaramov N, Atanasova S, Toncheva D, Oellerich M, von Ahsen N. No association between MDR1 (ABCB1) 2677G>T and 3435C>T polymorphism and sporadic colorectal cancer among Bulgarian patients. J Cancer Res Clin Oncol 2007; 134:317-22. [PMID: 17674045 DOI: 10.1007/s00432-007-0279-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2006] [Accepted: 07/03/2007] [Indexed: 02/06/2023]
Abstract
PURPOSE Variation in genetic factors together with xenobiotic exposure may result in increased risk of colorectal cancer. The P-glycoprotein (P-gp) is highly expressed in the apical membrane of enterocytes, where it pumps xenobiotics from the enterocytes back into the intestinal lumen. Thus, polymorphisms that reduce the activity of the MDR1 (ABCB1) efflux pump are potential risk factors for colorectal carcinogenesis. The aim of the present study is to genotype the MDR1 2677G>T (rs2032582) and 3435C>T (rs1045642) polymorphism in patients with colorectal cancer and controls and to identify a possible association between individual genetic variation and susceptibility to colorectal cancer. METHODS In the present study, 146 Bulgarian patients with sporadic colorectal cancer and 160 healthy Bulgarian volunteers were evaluated for the two polymorphisms in MDR1. Polymorphisms were identified using rapid-cycle real-time amplification with allele-specific probes and subsequent melting curve analyses on a LightCyclertrade mark (Roche Diagnostics, Mannheim, Germany). RESULTS No differences were found between the frequencies of the two mutant alleles in the tumor tissue from the cases and lymphocytes from the controls [frequencies of 2677T: 43.5% in patients and 44.1% in controls; frequencies of 3435T: 48.3% in patients and 50.9% in controls (both P > 0.05)]. The MDR1 polymorphic sequence of the tumor tissue always matched that of normal intestinal tissue from the same patient. Consequently, genotyping of DNA from archived tumor tissues is a valid alternative to the use of leukocyte DNA. CONCLUSIONS The present study suggests that MDR1 2677G>T and 3435C>T polymorphism is not a risk factor for sporadic colon cancer among Bulgarians and that somatic mutation at these sites is not involved in the genesis of colon tumors. Further examination using larger number of samples must be necessary to reach to more reliable conclusions.
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40
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Fischer S, Lakatos PL, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Szilvasi A, Tulassay Z, Osztovits J, Papp J, Demeter P, Schwab R, Tordai A, Andrikovics H. ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgeryin Hungarian patients with inflammatory bowel diseases. Scand J Gastroenterol 2007; 42:726-733. [PMID: 17505995 DOI: 10.1080/00365520601101559] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE MDR1 (ABCB1), a member of the ATP-binding cassette (ABC) transporters, is an attractive candidate gene for the pathogenesis of inflammatory bowel diseases (IBD) and perhaps for response to therapy. Since limited data are available on MDR1 and ABCG2 polymorphisms in East European IBD patients, the aim of this study was to investigate ABCG2 and MDR1 variants and responses to medical therapy and/or disease phenotype in Hungarian patients. MATERIAL AND METHODS A total of 414 unrelated IBD patients (Crohn's disease (CD): 265, age: 35.2+/-12.1 years, duration: 8.7+/-7.6 years and ulcerative colitis (UC): 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. ABCG2 G34A, C421A and MDR1 C3435T, G2677T/A single nucleotide polymorphisms (SNPs) were detected using real-time polymerase chain reaction (PCR). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS The frequency of the ABCG2 and MDR1 SNPs was not significantly different among IBD, CD, UC patients and controls. There was no difference in risk for steroid resistance in CD patients carrying variant ABCG2 (19.6% versus non-carriers 18.4%, p=NS) or MDR1 3435T (CC: 22.2% versus CT/TT: 17.6%) alleles. In addition, carriage of the variant allele was not associated with disease phenotype, presence of extra-intestinal manifestations, smoking, response to infliximab therapy or the need for surgery. In UC, the carriage of variant ABCG2 alleles seemed to be preventive for arthritis (15.5% versus 31.7%, OR: 0.39, 95% CI: 0.16-0.98). CONCLUSIONS MDR1 and ABCG2 SNPs were not associated with disease susceptibility or disease phenotype in Hungarian patients, and variant alleles did not predict the response to medical therapy or the need for surgery. Further studies are needed to clarify the association between the presence of ABCG2 variants and arthritis in UC.
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Affiliation(s)
- Simon Fischer
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
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41
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Mendoza JL, Urcelay E, Lana R, Martín MC, López N, Guijarro LG, Mayol JA, Taxonera C, de la Concha EG, Peña AS, Díaz-Rubio M. MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's disease. Inflamm Bowel Dis 2007; 13:585-590. [PMID: 17262810 DOI: 10.1002/ibd.20044] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohn's disease (CD). METHODS A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case-control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid-dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. RESULTS A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6-12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8-22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8-fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82-3.9; P = 0.14). CONCLUSIONS The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy.
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Affiliation(s)
- Juan L Mendoza
- Department of Gastroenterology, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain.
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42
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Ardizzone S, Maconi G, Bianchi V, Russo A, Colombo E, Cassinotti A, Penati C, Tenchini ML, Bianchi Porro G. Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:516-23. [PMID: 17260353 DOI: 10.1002/ibd.20108] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. METHODS A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype-phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. RESULTS No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34-8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20-0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13-0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. CONCLUSIONS The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host-bacteria interactions and in the pathogenesis of IBD.
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Affiliation(s)
- S Ardizzone
- Department of Gastroenterology L. Sacco University Hospital, University of Milan, Milan, Italy.
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43
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Van Limbergen J, Russell RK, Nimmo ER, Ho GT, Arnott ID, Wilson DC, Satsangi J. Genetics of the innate immune response in inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:338-55. [PMID: 17206667 DOI: 10.1002/ibd.20096] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins.
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Affiliation(s)
- Johan Van Limbergen
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
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Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 2007; 39:177-99. [PMID: 17457716 DOI: 10.1080/07853890701197615] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
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Affiliation(s)
- Philippe Goyette
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
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45
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Lal S, Stempak JM, Law C, Elkadri AA, Steinhart AH, Silverberg MS. Association between the C3435T polymorphism of the MDR1 gene and Crohn's disease. Inflamm Bowel Dis 2006; 12:1006-7. [PMID: 17012973 DOI: 10.1097/01.mib.0000228999.37090.e1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Annese V, Valvano MR, Palmieri O, Latiano A, Bossa F, Andriulli A. Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis. World J Gastroenterol 2006; 12:3636-3644. [PMID: 16773678 PMCID: PMC4087454 DOI: 10.3748/wjg.v12.i23.3636] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2006] [Revised: 02/28/2006] [Accepted: 04/16/2006] [Indexed: 02/06/2023] Open
Abstract
The MDR1 gene is an attractive candidate gene for the pathogenesis of inflammatory bowel disease (IBD) and perhaps response to therapy, with evidences at both functional and genetic levels. Its product, the P-glycoprotein (P-gp) functions as a transmembrane efflux pump thus influencing disposition and response of many drugs, some of whom (i.e. glucocorticoids) central to IBD therapy. In addition P-gp is highly expressed in many epithelial surfaces, included gastrointestinal tract (G-I) with a putative role in decreasing the absorption of endogenous or exogenous toxins, and perhaps host-bacteria interaction. Many genetic variations of MDR1 gene has been described and in some instances evidences for different P-gp expression as well drugs metabolism have been provided. However data are often conflicting due to genetic heterogeneity and different methodologies employed. Perhaps the greatest piece of evidence of the physiological importance of P-gp in the G-I tract has come from the description of the mdr1 knock-out mice model, which develops a spontaneous colitis in a specific pathogen-free environment. Studies investigating MDR1 gene polymorphism and predisposition to IBD have also shown conflicting results, owing to the known difficulties in complex diseases, especially when the supposed genetic contribution is weak. In this study we have undertaken a meta-analysis of the available findings obtained with two SNPs polymorphism (C3435T and G2677T/A) in IBD; a significant association of 3435T allele and 3435TT genotype has been found with UC (OR = 1.17, P = 0.003 and OR = 1.36, P = 0.017, respectively). In contrast no association with CD and the G2677T/A polymorphism could be demonstrated.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology
- Alleles
- Animals
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/physiopathology
- Gene Expression Regulation
- Genes, MDR/genetics
- Genes, MDR/physiology
- Humans
- Inflammatory Bowel Diseases/genetics
- Inflammatory Bowel Diseases/physiopathology
- Intestinal Mucosa/chemistry
- Intestinal Mucosa/physiopathology
- Mice
- Mice, Knockout
- Polymorphism, Single Nucleotide/genetics
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Affiliation(s)
- V Annese
- Unità di Gastroenterologia, Ospedale IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (Fg), Italy.
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