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Bazid HAS, Hammam MA, Keshk MH, Mostafa ML, Abd El Gayed EM. N-Acetyltransferase 2 gene polymorphism and its serum levels in vitiligo patients. J Immunoassay Immunochem 2024; 45:518-528. [PMID: 39404470 DOI: 10.1080/15321819.2024.2415898] [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] [Indexed: 11/20/2024]
Abstract
BACKGROUND Although numerous mechanisms are involved in vitiligo pathogenesis, few studies correlate N-acetyltransferase 2 to this disease. AIM To assess the N-acetyltransferase 2 (rs1799929) gene and its serum levels in vitiligo patients. SUBJECTS AND METHODS In this case-control study, 65 vitiligo cases were compared to 65 age- and sex-matched healthy controls. Serum NAT2 levels and the NAT2 gene polymorphism (rs1799929) were evaluated using ELISA and real-time PCR, respectively. RESULTS Serum N-acetyltransferase 2 levels were significantly lower in cases than in controls, 1.24 ± 0.31 vs. 2.01 ± 0.46 (p = 0.001). CC genotype was more dominant in controls (58.5%) than in cases (20%). TT and CT genotypes were more dominant in cases (30.8% and 49.2%) than in controls (13.8% and 27.7%), respectively (p = 0.001). The C allele was more prominent in controls (72.3%) than in cases (44.6%) while the T allele was more dominant in cases (55.4%) than in controls (27.7%) (p = 0.001). N-acetyltransferase 2 slow acetylator phenotype (TT genotype) was higher in cases (30.8%) than in controls (13.8%) and rapid acetylator phenotypes (CC and CT genotypes) were higher in controls (86.2%) than in cases (69.2%) (p = 0.035). CONCLUSION Slow acetylator genotype (TT) of NAT2 gene (rs1799929) and low serum levels of NAT2 enzyme might play a role in the susceptibility and pathogenesis of vitiligo.
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Affiliation(s)
- Heba A S Bazid
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
| | - Mostafa A Hammam
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
| | - Mona H Keshk
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Shebin Elkom, Egypt
| | - Mohammed L Mostafa
- Clinical Pathology Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Eman M Abd El Gayed
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Shibin El Kom, Egypt
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Giriyappagoudar M, Vastrad B, Horakeri R, Vastrad C. Study on Potential Differentially Expressed Genes in Idiopathic Pulmonary Fibrosis by Bioinformatics and Next-Generation Sequencing Data Analysis. Biomedicines 2023; 11:3109. [PMID: 38137330 PMCID: PMC10740779 DOI: 10.3390/biomedicines11123109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/31/2023] [Accepted: 11/02/2023] [Indexed: 12/24/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next-generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed. Using the g:Profiler, the function and pathway enrichment analyses of DEGs were performed. Then, a protein-protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst databaseswereused to construct the targeted microRNAs (miRNAs), transcription factors (TFs), and small drug molecules. Finally, receiver operating characteristic (ROC) curve analysis was used to validate the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process, and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8, and EFHC2 were selected. Cyclothiazide and rotigotinethe are predicted small drug molecules for IPF treatment. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.
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Affiliation(s)
- Muttanagouda Giriyappagoudar
- Department of Radiation Oncology, Karnataka Institute of Medical Sciences (KIMS), Hubballi 580022, Karnataka, India;
| | - Basavaraj Vastrad
- Department of Pharmaceutical Chemistry, K.L.E. Socitey’s College of Pharmacy, Gadag 582101, Karnataka, India;
| | - Rajeshwari Horakeri
- Department of Computer Science, Govt First Grade College, Hubballi 580032, Karnataka, India;
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India
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Saghaeian Jazi M, Mohammadi S, Zare Ebrahimabad M, Sedighi S, Abdolahi N, Tabarraei A, Yazdani Y. Genetic variation in CYP1A1 and AHRR genes increase the risk of systemic lupus erythematosus and exacerbate disease severity in smoker patients. J Biochem Mol Toxicol 2021; 35:e22916. [PMID: 34580959 DOI: 10.1002/jbt.22916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 08/18/2021] [Accepted: 09/01/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Genetic variations of aryl hydrocarbon receptor (AHR) pathway genes could influence the imbalanced immune response to xenobiotics. Therefore, we aimed to investigate the polymorphism of AHR pathway genes in systemic lupus erythematosus (SLE) patients in association with smoking. METHODS Genomic DNA from patients (N = 107) and controls (N = 105) of a population from northeast of Iran was used for genotyping of CYP1A1 T>C (rs4646903) and AHRR C>G (rs2292596) variants. The SLEDAI score and smoking status of the patients were registered. The AHR activity was estimated by CYP1A1 and CYP1B1 gene expression in peripheral blood mononuclear cells (PBMC). RESULTS The C allele in rs4646903 (odds ratio [OR] = 2.67) and G allele in rs2292596 (OR = 1.79) SNPs were significantly associated with the increased risk of SLE. The AHR pathway was more active in high-risk CYP1A1/AHRR: C/G haplotype. The most severe disease was observed in smoker patients with high-risk haplotype and both smoking (Exp (β) = 9.5) and high-risk CYP1A1/AHRR (C/G) haplotype (Exp (β) = 3.7) can significantly increase the likelihood of having severe (SLEDAI ≥ 20) SLE disease activity. CONCLUSION Our findings indicated the association of xenobiotic-metabolizing genes (CYP1A1, AHRR) polymorphisms with the susceptibility to SLE and disease severity regarding the smoking background, suggesting the interaction of gene and environmental risk factors in SLE pathogenesis.
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Affiliation(s)
- Marie Saghaeian Jazi
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Saeed Mohammadi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mojtaba Zare Ebrahimabad
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Biochemistry, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sima Sedighi
- Golestan Rheumatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Nafiseh Abdolahi
- Golestan Rheumatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Alijan Tabarraei
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Yaghoub Yazdani
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on T Cell Differentiation in Primary Biliary Cholangitis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1754975. [PMID: 32908870 PMCID: PMC7468604 DOI: 10.1155/2020/1754975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 07/12/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022]
Abstract
Exposure to dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is reported to affect the autoimmune system and increase the risk of autoimmune disease. Generally, dioxin exerts its toxicity via aryl hydrocarbon receptor (AhR). Primary biliary cholangitis (PBC) is a chronic autoimmune disease, and its pathogenesis involves the interplay between immune and environmental factors. This study showed the effect of dendritic cells (DCs) activated by TCDD on naïve CD4+ T cell differentiation in patients with PBC. CD14+ mononuclear cells were isolated from peripheral blood mononuclear cells (PBMCs) of patients with PBC and healthy people by magnetic cell separation and introduced into DCs. Two days after stimulation by TCDD, DCs were cocultured with naïve CD4+ T cells in a ratio of 1 : 2 for 3 days. Then, differentiation-related factors for naïve CD4+ T cells were detected by real-time fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and flow cytometry. The results showed that TCDD-activated DCs could promote Th1 and Th17 differentiation in patients with PBC. Therefore, this study demonstrated TCDD as an AhR agonist in regulating naïve CD4+ T cell differentiation in patients with PBC.
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Srivastava DSL, Aggarwal K, Singh G. Is NAT2 Gene Polymorphism Associated with Vitiligo? Indian J Dermatol 2020; 65:173-177. [PMID: 32565555 PMCID: PMC7292445 DOI: 10.4103/ijd.ijd_388_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background: N-acetyltransferase-2 (NAT2) is a phase II xenobiotic enzyme that plays an important role against oxidative stress-mediated reactive oxygen species protection. Polymorphism in specific genotypes of NAT2 may lead to increase an imbalance in antioxidant systems and may influence the pathogenesis of vitiligo. We conducted this study to see the association between NAT2 gene polymorphism and risk of vitiligo. We looked into whether single-nucleotide polymorphisms (SNP) at positions 857, 481 and 590 of the coding region of the NAT2 gene play as a risk factor for vitiligo among north Indian people. Methods: In this study, we assessed 100 patients with vitiligo and 160 healthy individuals as controls. Genomic DNA was extracted from human peripheral blood and polymerase chain reaction–restricted fragment length polymorphism was done to identify the single nucleotide polymorphism at positions 857, 481, and 590 of the coding region of the NAT2 gene. Results: In this study, we observed a significant higher risk with slow acetylator genotypes of NAT2 (OR = 2.85; 95% CI = 1.68-4.84, P value < 0.001) for the vitiligo. Furthermore, in the association between NAT2 acetylator genotypes with percentage of body surface area (BSA) of disease, we observed that slow acetylator genotypes of NAT2 has significant higher risk with low grade of disease (1%–10% >11%–30% >30% of BSA). Limitations: A major limitation of this study was the small sample size and warrants further investigation on a large epidemiological study to confirm these findings. Conclusions: Our preliminary data indicate that NAT2 slow acetylator genotype exhibits significant association for the risk of vitiligo, especially in disease predisposition and initiation.
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Affiliation(s)
- Daya Shankar Lal Srivastava
- Department of BTMM and Biochemistry, PGIMS, Pt. B.D. Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Kamal Aggarwal
- Department of Skin and VD, PGIMS, Pt. B.D. Sharma University of Health Sciences, Rohtak, Haryana, India
| | - Gajendra Singh
- College of Pharmacy, PGIMS, Pt. B.D. Sharma University of Health Sciences, Rohtak, Haryana, India
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Saiz PA, Garcia-Portilla MP, Arango C, Morales B, Alvarez V, Coto E, Fernandez JM, Bousono M, Bobes J. N-acetyltransferase-2 polymorphisms and schizophrenia. Eur Psychiatry 2020; 21:333-7. [PMID: 16529914 DOI: 10.1016/j.eurpsy.2005.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2005] [Accepted: 12/15/2005] [Indexed: 11/22/2022] Open
Affiliation(s)
- Pilar Alejandra Saiz
- School of Medicine, University of Oviedo, Department of Psychiatry, Julian Claveria 6 - 3th, 33006, Oviedo, Asturias, Spain.
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Barańska M, Rychlik-Sych M, Kaszuba A, Dziankowska-Bartkowiak B, Skrętkowicz J, Waszczykowska E. Genetic polymorphism of CYP2D6 in patients with systemic lupus erythematosus and systemic sclerosis. Autoimmunity 2016; 49:166-171. [PMID: 26789496 DOI: 10.3109/08916934.2015.1134508] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 12/16/2015] [Indexed: 01/19/2023]
Abstract
Human organism is constantly exposed to harmful exogenous factors (xenobiotics) including drugs and carcinogenic compounds that can induce development of a large number of diseases. The processes of biotransformation in the organism are multidirectional and xenobiotics can be transformed into active or inactive metabolites via the oxidative route. The knowledge of oxidation polymorphism in the course of systemic lupus erythematosus and systemic sclerosis may be helpful in choosing more efficient and safer therapy, particularly in the case of a disease involving various organs and treated with drugs belonging to diverse therapeutic groups. The aim of the study was to evaluate the CYP2D6 polymorphism in the SLE (systemic lupus erythematosus) and SSc (systemic sclerosis) patients and to investigate a possible correlation with disease susceptibility. The study was carried out in 296 patients: 65 patients with SLE, 81 patients with SSc, and 150 healthy volunteers. The CYP2D6 genotypes were analyzed by polymerase chain reaction fragment length polymorphism (PCR-RFLP) method. The relative risk of developing SSc, expressed by the odds ratio, was three-fold higher for persons with the CYP2D6*1/CYP2D6*4 genotype (OR = 2.9; statistically significant difference, p = 0.0002). A statistically significant correlation between the CYP2D6*4 allele prevalence and the risk for developing SSc was found (OR = 1.53; p = 0.047). No effect of the CYP2D6 gene mutations on the incidence of SLE was noted. The obtained results may suggest the influence of CYP2D6*4 gene variants alleles on increased incidence of systemic sclerosis.
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Affiliation(s)
- Małgorzata Barańska
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódź, Poland and
| | - Mariola Rychlik-Sych
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódź, Poland and
| | - Andrzej Kaszuba
- Department of Dermatology and Pediatric Dermatology and Oncology, Medical University of Lodz, Łódź, Poland, and
| | | | - Jadwiga Skrętkowicz
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódź, Poland and
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Glesse N, Rohr P, Monticielo OA, Rech TF, Brenol JCT, Xavier RM, Kvitko K, Chies JAB. Genetic polymorphisms of glutathione S-transferases and cytochrome P450 enzymes as susceptibility factors to systemic lupus erythematosus in southern Brazilian patients. Mol Biol Rep 2014; 41:6167-79. [DOI: 10.1007/s11033-014-3496-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 06/17/2014] [Indexed: 01/05/2023]
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Different Roads, Same Destination. J Invest Dermatol 2014; 134:1154-1155. [DOI: 10.1038/jid.2014.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Genetic polymorphisms of CYP2D6 oxidation in patients with autoimmune bullous diseases. Postepy Dermatol Alergol 2013; 30:211-7. [PMID: 24278077 PMCID: PMC3834712 DOI: 10.5114/pdia.2013.37030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 03/15/2013] [Accepted: 04/29/2013] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Bullous skin diseases, which include, among others pemphigoid, pemphigus, and dermatitis herpetiformis are classified as severe autoimmune dermatoses. It has been shown that a pattern of xenobiotic metabolism may play a role in the pathogenesis of autoimmune diseases. AIM To estimate whether the CYP2D6 genotype may be considered a predisposing factor in autoimmune bullous diseases induction. MATERIAL AND METHODS The study included 72 patients with autoimmune bullous diseases: 37 with pemphigoid, 21 with pemphigus, and 14 with dermatitis herpetiformis (DH). The CYP2D6 genotypes were analyzed by the polymerase chain reaction fragment length polymorphism (PCR-RFLP) method. RESULTS Relative risk of DH development for particular genotype carriers expressed by odds ratio (OR) was statistically significantly higher for subjects with CYP2D6*1/CYP2D6*4 (OR = 4.2; p = 0.0104) and 2-fold higher for subjects with CYP2D6*4 (OR = 2.3; p = 0.0351). CONCLUSIONS The results of the present study show that the CYP2D6 oxidation polymorphism cannot be considered a risk factor for development of pemphigoid and pemphigus, however it might have an impact on dermatitis herpetiformis.
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Oqal MK, Mustafa KN, Irshaid YM. N-acetyltransferase-2 genotypes among patients with rheumatoid arthritis attending Jordan University Hospital. Genet Test Mol Biomarkers 2012; 16:1007-10. [PMID: 22731637 DOI: 10.1089/gtmb.2012.0062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIM To determine the frequency of major N-acetyltransferase (NAT2) alleles and genotypes among Jordanian patients with rheumatoid arthritis (RA). METHODS The study was approved by the IRB of the Jordan University Hospital. An informed consent was signed by every patient. DNA samples from 150 healthy volunteers and 108 patients with RA were analyzed by polymerase chain reaction followed by a restriction fragment length polymorphism assay (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6, and NAT2*7. RESULTS The most prevalent genotypes are those that encode the slow acetylation phenotype. About 59.3% of the patients with RA carried the slow, 33.3% the intermediate, and 7.4% the fast-encoding genotypes. The frequency of NAT2 alleles was 0.241 (95% confidence interval [CI] 0.184-0.298) for NAT2*4, 0.449 (95% CI 0.383-0.515) for NAT2*5, 0.273 (95% CI 0.214-0.332) for NAT2*6, and 0.037 (95% CI 0.012-0.062) for NAT2*7 allele. The overall frequency of the slow acetylation genotype in patients with RA is similar to that in healthy Jordanian volunteers. However, the NAT2*5/7 genotype was found in seven patients (6.5%) with RA and was absent in Jordanian volunteers, and the z test revealed that the difference was statistically significant. This genotype constituted 10.9% of the genotypes encoding slow acetylation. CONCLUSION The overall acetylator genotype in RA is similar to that in healthy volunteers. The overall slow acetylator genotypes do not seem to be a genetic risk factor for RA among Jordanians. However, the NAT2*5/7 genotype seems to be related to RA. The nature of this relationship needs further clarification.
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Affiliation(s)
- Muna K Oqal
- Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman, Jordan
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Significance of genetic polymorphism of CYP2D6 in the pathogenesis of systemic sclerosis. Pharmacol Rep 2012; 64:336-42. [DOI: 10.1016/s1734-1140(12)70773-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Revised: 12/05/2011] [Indexed: 12/13/2022]
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Dar SA, Das S, Ramachandran VG, Bhattacharya SN, Mustafa MD, Banerjee BD, Verma P. Alterations in T-lymphocyte sub-set profiles and cytokine secretion by PBMC of systemic lupus erythematosus patients upon in vitro exposure to organochlorine pesticides. J Immunotoxicol 2012; 9:85-95. [PMID: 22214240 DOI: 10.3109/1547691x.2011.642103] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Chronic exposure to organochlorine pesticides (OCP) has been suspected of causing immunoregulatory abnormalities that eventually lead to development and progression of systemic lupus erythematosus (SLE), but the role of these non-genetic stimuli has remained poorly understood. The objectives of the study were to quantify the levels of different OCP residues in the blood of SLE patients and to study the effects of in vitro treatment of peripheral blood mononuclear cells (PBMC) from these patients and healthy controls with OCP. Levels of different OCP residues in the blood were measured by gas-liquid chromatography. Isolated PBMC were treated in vitro with hexachlorocyclohexane (HCH), o,p'-dichlorodiphenyltrichloroethane (DDT), or phytohemagglutinin-M (PHA-M) for 72 h, then stained with different dye-labeled monoclonal antibodies to analyze alterations in T-lymphocytes using flow cytometry. Levels of different T(H)1 and T(H)2 cytokines were also estimated by ELISA. Significantly higher levels of p,p'-DDE and β-HCH were detected in the blood of SLE patients than in healthy controls. HCH exposure markedly increased the percentages of CD3(+)CD4(+) T-lymphocytes and expression of CD45RO(+) on CD4(+) and CD8(+) T-lymphocytes, but decreased CD4(+)CD25(+) T-lymphocytes in SLE patients. DDT exposure increased the percentages of CD3(+)CD4(+) T-lymphocytes and decreased those of CD4(+)CD25(+) T-lymphocytes in SLE patients as compared to healthy controls. No significant responsiveness of patient PBMC to PHA-M stimulation was observed indicating suppression of T-lymphocytes by these OCP. Further, both HCH and DDT decreased the levels of IL-2 and IFNγ but had no effect on IL-4 levels in SLE patients. DDT also increased significantly the levels of IL-10 in patients. It is likely that higher levels and prolonged durations of exposure to HCH and DDT may significantly influence T-lymphocyte sub-sets and cytokine expression in vivo that could lead to the development or exacerbation of SLE.
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Kiyohara C, Washio M, Horiuchi T, Asami T, Ide S, Atsumi T, Kobashi G, Takahashi H, Tada Y. Risk modification byCYP1A1andGSTM1polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population. Scand J Rheumatol 2012; 41:103-9. [DOI: 10.3109/03009742.2011.608194] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Semiz S, Dujic T, Ostanek B, Velija-Asimi Z, Prnjavorac B, Bego T, Malenica M, Mlinar B, Heljic B, Marc J, Causevic A. Association of NAT2 polymorphisms with type 2 diabetes in a population from Bosnia and Herzegovina. Arch Med Res 2011; 42:311-7. [PMID: 21820610 DOI: 10.1016/j.arcmed.2011.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Accepted: 06/09/2011] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS N-acetyltransferase 2 (NAT2) is a drug-metabolizing enzyme, which is genetically variable in human populations. Polymorphisms in the NAT2 gene have been associated with drug efficacy and toxicity as well as disease susceptibility. Recently, an association of NAT2 gene variation with risk of type 2 diabetes mellitus (T2DM) has been suggested. This is the first study performed in a population from Bosnia and Herzegovina (BH) in which the frequency of two common NAT2 polymorphisms, 341T>C (NAT2*5) and 590G>A (NAT2*6) was determined in diabetic patients. METHODS The frequency of the NAT2*5 (341T>C) and NAT2*6 (590G>A) polymorphisms was analyzed by employing TaqMan SNP Genotyping Assays (Applied Biosystems) in a group of 63 patients with T2DM and 79 nondiabetic subjects. RESULTS Our data demonstrated that the frequencies of NAT2*5 (341T>C) and NAT2*6 (590G>A) polymorphisms in BH population were in line with the Caucasians genotype data. The NAT2*5 and NAT2*6 alleles were in high linkage disequilibrium (D' = 0.969). Strinkingly, there was a significant difference in genotype frequencies for NAT2*5 (p <0.05) and NAT2*6 (p <0.001) polymorphisms between diabetic and nondiabetic subjects. NAT2*5 polymorphism was associated with 2.4-fold increased risk for developing T2DM (adjusted OR = 2.40, 95% CI = 1.10-5.25, p = 0.028). On the contrary, NAT2*6 variant significantly decreased by 5-fold susceptibility to the disease (adjusted OR = 0.20, 95% CI = 0.09-0.43, p <0.001). CONCLUSIONS Our data demonstrated that NAT2 genetic variation appeared to be an important risk factor in development of T2DM.
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Affiliation(s)
- Sabina Semiz
- Department of Biochemistry and Clinical Analysis, Faculty of Pharmacy, University of Sarajevo, Bosnia and Herzegovina.
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Chen X, Abdulhamid I, Woodcroft K. Maternal smoking during pregnancy, polymorphic CYP1A1 and GSTM1, and lung-function measures in urban family children. ENVIRONMENTAL RESEARCH 2011; 111:1215-1221. [PMID: 21872227 DOI: 10.1016/j.envres.2011.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Revised: 07/29/2011] [Accepted: 08/02/2011] [Indexed: 05/31/2023]
Abstract
PURPOSE Understanding the interplay between genes and in-utero tobacco exposure in affecting child lung development is of great significance. In this study, we tested the hypothesis that tobacco-related lung-function reduction in children differs by maternal polymorphic genes Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase Mu 1 (GSTM1). MATERIALS AND METHODS Data were collected among 370 children (6-10 years old, 81.6% African-Americans) and their biological mothers visiting a large children's hospital. Study hypotheses were tested using multiple regression method. RESULTS Among the study sample, 143 mothers smoked throughout pregnancy and 72 smoked on a daily basis. Spirometric measures (mean±SD) included were: forced vital capacity (FVC)=1635±431 mL, forced expiratory volume in the first 1s (FEV1)=1440 ±360 mL, percent FEV1/FVC ratio=89±12, and forced expiratory flow between the 25% and 75% of FVC (FEF25-75)=1745±603 mL. In addition to a tobacco effect on FVC (-131 mL, 95% CI: -245, -17) and FEV1/FVC ratio (42, 95% CI: 1, 83), regression analysis controlling for covariates indicated that for the subsample of children whose mothers were CYP1A1⁎2A homozygous, maternal daily smoking was associated with -734 mL (95% CI: -1206, -262) reductions in FEV1 and -825 mL (95% CI: -909, -795) reductions in FVC; reduced smoking was still associated with -590 mL (95% CI: -629, -551) reductions in FVC. For children of mothers with GSTM1 deletion, persistent daily smoking was associated with -176 mL (95% CI: -305, -47) reductions in FVC. DISCUSSION AND CONCLUSIONS Maternal smoking during pregnancy was significantly associated with lung-function reduction in children, particularly for those whose mothers possessed the polymorphic CYP1A1*2A and GSTM1 deletion.
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Affiliation(s)
- Xinguang Chen
- The Adams Ann Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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Skrętkowicz J, Barańska M, Kaczorowska A, Rychlik-Sych M. Genetic polymorphisms of CYP2D6 oxidation in patients with systemic lupus erythematosus. Arch Med Sci 2011; 7:864-9. [PMID: 22291833 PMCID: PMC3258794 DOI: 10.5114/aoms.2011.25563] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 07/14/2010] [Accepted: 08/26/2010] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Systemic lupus erythematosus (SLE) is a complex, multifactor autoimmune disease. The studies on aetiopathogenesis of autoimmune diseases focus on the impact the genetically conditioned impairment of xenobiotic metabolism may exert. The knowledge of oxidation polymorphism in the course of SLE may be helpful in choosing more efficient and safer therapy. We determined whether there was an association between susceptibility to SLE and particularly to CYP2D6 genotypes. MATERIAL AND METHODS The study was carried out in 60 patients with SLE and 129 healthy volunteers and all the subjects were of Polish origin. The samples were analysed for two major defective alles for CYP2D6 - CYP2D6*3 and CYP2D6*4 and one wild -type allele CYP2D6*1-by the polymerase chain reaction fragment length polymorphism (PCR-RFLP) metod with DNA extracted from peripheral blood. RESULTS No statistically significant differences in the incidence of CYP2D6 genotypes between the studied groups were found (p = 0.615). Risk (OR) of SLE development was 1.03 for the carriers of CYP2D6*3 allele and 1.48 for the subjects with CYP2D6*4 allele; but it was not statistically significant. CONCLUSIONS Increased occurrence of mutant alleles of the CYP2D6 gene in SLE patients and the calculated OR values could suggest the effect of these mutations on increased SLE development.
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Affiliation(s)
| | - Małgorzata Barańska
- Department of Pharmacogenetics, Medical University of Lodz, Poland
- Corresponding author: Małgorzata Barańska MD, PhD, Department of Pharmacogenetics, Medical University of Lodz, 1 Muszyńskiego, 90-151 Lodz, Poland, Phone: +48 42 6779177, Fax: +48 42 6788398. E-mail:
| | - Anna Kaczorowska
- Department of Dermatology and Paediatric Dermatology, Military-Medical Faculty, Medical University of Lodz, Poland
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Abstract
Every organism is in contact with numerous small molecules (<1000 Da). Chemicals may cause or trigger adverse health effects, including diseases of the immune system. They may also be exploited as drugs. In this review, we look at the interaction between small molecules and the immune system. We discuss the hapten and pharmacological interaction concepts of chemical interaction to trigger T cells and how chemicals can participate in cellular signaling pathways. As a sensor of small molecules, the arylhydrocarbon receptor controls expression of many xenobiotic metabolizing enzymes, including those in the immunological barrier organs; the skin and gut. The relevance of the arylhydrocarbon receptor in the dynamic interaction of the immune system with the chemical environment is therefore discussed.
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External influences on the immune system via activation of the aryl hydrocarbon receptor. Semin Immunol 2011; 23:99-105. [PMID: 21288737 DOI: 10.1016/j.smim.2011.01.008] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Accepted: 01/10/2011] [Indexed: 02/06/2023]
Abstract
The aryl hydrocarbon receptor (AhR), subject of intensive research over three decades by the pharmacology/toxicology field has recently made its entry into mainstream immunology research and is set to continue to intrigue with ever more complex modes of modulating immune responses. The discovery of high and selective AhR expression on Th17 cells and its role in induction of the cytokine IL-22 attributed new immunological functions to this transcription factor and stimulated further research into physiological functions of the AhR in the immune system. A number of recent reviews have highlighted potential new avenues of research. This review addresses recent new insight into physiological roles of AhR in the immune system.
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20
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Khelil M, Zenati A, Makrelouf M, Otmane A, Tayebi B. Polymorphisms in NAT2 gene and atherosclerosis in an Algerian population. Arch Med Res 2010; 41:215-20. [PMID: 20682180 DOI: 10.1016/j.arcmed.2010.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 03/19/2010] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND AIMS The etiology of atherosclerosis is multifactorial. Genetic and environmental factors are involved in the development of atherosclerosis. Human arylamine N-acetyltransferase 2 (NAT2) is an important metabolizing enzyme that exhibits genetic polymorphisms and modifies individual response and/or toxicity to many xenobiotics. We undertook this study to investigate the NAT2 polymorphisms in patients with atherosclerosis. METHODS Genotyping for NAT2 alleles was performed using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) in 285 Algerian patients with atherosclerosis and 286 controls. RESULTS There was no association between NAT2 polymorphisms and atherosclerosis risk. However, the haplotype NAT2(*)5F decreased susceptibility to the disease (p = 0.005, OR = 0.55, 95% CI = 0.37-0.84). The frequency of the slow acetylator phenotype was approximately 50% in both cases and controls. CONCLUSIONS These results suggest that NAT2 polymorphisms may not be involved in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Malika Khelil
- Département de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari, Boumediène, Alger, Algérie.
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Zhang J, Deng J, Zhang C, Lu Y, Liu L, Wu Q, Shao Y, Zhang J, Yang H, Yu B, Wan J. Association of GSTT1, GSTM1 and CYP1A1 polymorphisms with susceptibility to systemic lupus erythematosus in the Chinese population. Clin Chim Acta 2010; 411:878-81. [PMID: 20226777 DOI: 10.1016/j.cca.2010.03.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2009] [Revised: 02/10/2010] [Accepted: 03/04/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND GSTT1, GSTM1, CYP1A1 are enzymes responsible for the detoxification of the toxicant which may be involved in the development of systemic lupus erythematosus (SLE). We examined the relationship between the risk of SLE and the polymorphisms of these genes in the Chinese population. METHODS Samples from 298 SLE patients and 284 healthy controls were collected. Polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotypes of CYP1A1 m2 and m4, while multiplex PCR was used to analyze the genotypes of GSTT1 and GSTM1. RESULTS Statistically significant difference was observed in genotypes for GSTM1 (p=0.003, OR 1.66 [95% CI 1.19-2.32]), but not for GSTT1 (p=0.119, OR 0.77 [95% CI 0.56-1.07]), in the SLE patients as compared with the controls. Combinational analysis for double-null deletion of both GSTT1 and GSTM1 showed no significant difference (p=0.863, OR 1.03 [95% CI 0.70-1.52]). Significant difference was observed in the genotype frequencies (p=0.013), but not in the allele frequencies (p=0.444, OR 0.90 [95% CI 0.70-1.17]), of CYP1A1 m2. All candidates have a wild-type genotype for CYP1A1 m4. CONCLUSIONS Polymorphisms of GSTM1 are associated with SLE in the Chinese population.
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Affiliation(s)
- Jufeng Zhang
- Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, 518036, China
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Esser C, Jux B. Small Chemicals, Bioactivation, and the Immune System â A Fragile Balance of i-Tox and Benefits? Chem Biodivers 2009; 6:2138-43. [DOI: 10.1002/cbdv.200900113] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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The aryl hydrocarbon receptor in immunity. Trends Immunol 2009; 30:447-54. [PMID: 19699679 DOI: 10.1016/j.it.2009.06.005] [Citation(s) in RCA: 349] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Revised: 05/26/2009] [Accepted: 06/11/2009] [Indexed: 12/16/2022]
Abstract
Low-molecular-weight chemicals or xenobiotics might contribute to the increasing prevalence of allergies and autoimmunity. Certain chemicals can alter immune responses via their action on the cytosolic transcription factor aryl hydrocarbon receptor (AhR). AhR recognizes numerous small xenobiotic and natural molecules, such as dioxin and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. Although AhR is best known for mediating dioxin toxicity, knockout studies have indicated that AhR also plays a role in normal physiology, including certain immune responses. In particular, Th17 cells and dendritic cells express high levels of AhR. We review here current evidence for the physiological role of AhR in the immune system, focussing in particular on T-cell biology.
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Horiuchi T, Washio M, Kiyohara C, Tsukamoto H, Tada Y, Asami T, Ide S, Kobashi G, Takahashi H. Combination of TNF-RII, CYP1A1 and GSTM1 polymorphisms and the risk of Japanese SLE: findings from the KYSS study. Rheumatology (Oxford) 2009; 48:1045-9. [PMID: 19561157 DOI: 10.1093/rheumatology/kep166] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Association of the polymorphisms of the genes, TNF receptor type II gene (TNF-RII), cytochrome P4501A1 gene (CYP1A1) and glutathione S-transferase M1 gene (GSTM1), with SLE was investigated. TNF-RII mediates inflammatory and immune response, whereas CYP1A1 and GSTM1 are involved in the metabolism of xenobiotics. These three genes are involved in the generation of reactive oxygen species (ROS), which play a critical role for autoimmune diseases. METHODS A total of 152 SLE patients and 427 healthy individuals in a female Japanese population were enrolled in the study. Case-control studies were performed for the polymorphisms of these three genes. RESULTS The carriers of TNF-RII 196R were at a significantly increased risk for SLE with odds ratio (OR) of 1.59 (95% CI = 1.01, 2.52). CYP1A1 3801C homozygotes had a significantly increased risk of SLE (OR = 2.47, 95% CI = 1.28, 4.78). On the other hand, GSTM1 null genotype was not associated with SLE risk. As for combination action of two loci, CYP1A1 3801C/GSTM1 null combination was more strongly associated with an increased risk of SLE (OR = 4.35; 95% CI = 1.76, 10.73). Moreover, TNF-RII 196M/CYP1A1 3801C/GSTM1 null genotype combination was most significantly associated with SLE (OR = 5.83; 95% CI = 2, 17.04). CONCLUSIONS The individuals carrying two or more 'at-risk' genotypes of TNF-RII, CYP1A1 and GSTM1 had a significantly more increased risk for SLE compared with those having each 'at-risk' genotype. Combination of the risk genotypes will be important to more clearly identify the population at risk for SLE.
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Affiliation(s)
- Takahiko Horiuchi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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25
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Genetic polymorphisms of CYP2D6 oxidation in patients with systemic sclerosis. Eur J Clin Pharmacol 2009; 65:971-6. [DOI: 10.1007/s00228-009-0662-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 04/27/2009] [Indexed: 10/20/2022]
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Kiyohara C, Washio M, Horiuchi T, Tada Y, Asami T, Ide S, Takahashi H, Kobashi G. Cigarette smoking, N-acetyltransferase 2 polymorphisms and systemic lupus erythematosus in a Japanese population. Lupus 2009; 18:630-8. [DOI: 10.1177/0961203309102809] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Cigarette smoking may be associated with an increased risk of systemic lupus erythematosus (SLE), but the underlying mechanism of this association remains unclear. N-acetyltransferase 2 (NAT2) is highly variable and detoxifies aromatic amines, an important class of carcinogens in tobacco smoke. Individuals who possess homozygous polymorphic alleles have a slower rate of metabolic detoxification of aromatic amines. We investigated the relationship of the NAT2 polymorphism to the risk of SLE with special reference to the interaction with cigarette smoking among 152 SLE cases and 427 controls in a female Japanese population. NAT2*4, NAT2*5B, NAT2*6A and NAT2*7B alleles were detected with polymerase chain reaction–restriction fragment length polymorphism. Individuals carrying the *4/*4 genotype are rapid acetylators, whereas those with homozygous non-*4 genotypes have a slow acetylator phenotype. Cigarette smoking was associated with an increased risk of SLE (odds ratio [OR] = 2.26; 95% confidence interval [CI] = 1.46–3.50). The slow acetylator genotype of NAT2 was significantly associated with an increased risk of SLE (OR = 2.34, 95% CI = 1.21–4.52) compared with the rapid acetylator genotype. A gene-environment interaction was suggested, with a combination of the NAT2 slow acetylator genotype and smoking conferring significantly higher risk (OR = 6.44, 95% CI = 3.07–13.52; attributable proportion due to interaction = 0.50, 95% CI = 0.12–0.88), compared with the NAT2 rapid acetylator genotype and no history of smoking. This study suggests that, in this Japanese population, the NAT2 slow acetylator status may be a determinant in susceptibility to SLE.
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Affiliation(s)
- C Kiyohara
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - M Washio
- Department of Community Health and Clinical Epidemiology, St. Mary’s College, Kurume, Japan
| | - T Horiuchi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Y Tada
- Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - T Asami
- Rehabilitation Center, Saga Medical School Hospital, Saga, Japan
| | - S Ide
- Department of Community Health and Clinical Epidemiology, St. Mary’s College, Kurume, Japan
| | - H Takahashi
- Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - G Kobashi
- Molecular Biostatistics Research Team, Research Center for Charged Particle Therapy, National Institute of Radiological Science, Chiba, Japan
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Chen X, Woodcroft KJ. Polymorphisms in metabolic genes CYP1A1 and GSTM1 and changes in maternal smoking during pregnancy. Nicotine Tob Res 2009; 11:225-33. [DOI: 10.1093/ntr/ntn027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
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Chaudhary S, Behari M, Dihana M, Swaminath PV, Govindappa ST, Jayaram S, Singh S, Muthane UB, Juyal RC, B K T. Association of N-acetyl transferase 2 gene polymorphism and slow acetylator phenotype with young onset and late onset Parkinson's disease among Indians. Pharmacogenet Genomics 2005; 15:731-5. [PMID: 16141799 DOI: 10.1097/01.fpc.0000173485.59430.49] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVES To investigate the association of (i) seven SNPs and SNP haplotypes in the phase II conjugating enzyme N-acetyl transferase 2 gene; and (ii) slow acetylator phenotype, with the development of young onset (YO) and late onset (LO) Parkinson's disease (PD) among Indians. METHODS A total of 267 cases (132 YOPD, age at onset < or =40 years; 135 LOPD, age at onset >40 years) and 324 age and sex matched controls (132 for YOPD and 192 for LOPD) were genotyped for NAT2 SNPs. Allelic, genotypic and haplotypic association was tested by chi2 using a case-control approach. Chi2 test of association of acetylation phenotype (by genotype) with PD was also carried out. RESULTS Of the seven SNPs genotyped, SNP191 was monomorphic and therefore, not included for analysis. With SNPs 590 and 857 a significant allelic [OR (95% CI) 4.147 (2.28-7.54) for A allele and 2.565 (1.34-4.92) for A allele, respectively] and genotypic [OR (95% CI) 0.27 (0.14-0.52) for GG and 0.35 (0.174-0.712) for GG, respectively] association with YOPD was observed. There was a significant allelic and genotypic association of SNP 282 with LOPD [chi2 = 8.92, P = 0.003 and chi2 = 10.2, P = 0.006, respectively]. There was also a significant association of protective and predisposing haplotypes TCGG and TCAG [OR (95% CI) 0.446 (0.31-0.63) and 3.742 (2.0-6.99), respectively] with YOPD and predisposing haplotype TCGA [OR (95% CI) 3.214 (1.43-7.22)] with LOPD. Slow acetylator phenotype was significantly associated with YOPD [OR (95% CI) 2.32 (1.2-4.48)]. CONCLUSION Specific SNPs and SNP haplotypes in NAT2 and slow acetylator phenotype are significantly associated with YOPD and to a lesser extent with LOPD among Indians.
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Affiliation(s)
- Shashi Chaudhary
- Department of Genetics, University of Delhi South Campus, New Delhi, India
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Sestak AL, Nath SK, Harley JB. Genetics of systemic lupus erythematosus: how far have we come? Rheum Dis Clin North Am 2005; 31:223-44, v. [PMID: 15922143 DOI: 10.1016/j.rdc.2005.01.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
There are two primary mechanisms for studying the genetic forces at work in systemic lupus erythematosus (SLE). Several groups have collected large numbers of pedigrees in which multiple family members have SLE for use in linkage studies. These linkage studies serve to isolate areas of the genome in which susceptibility genes lie. Other groups have taken a more direct approach of investigating genes that might contribute to disease pathogenesis in sets of lupus subjects and matched controls. These association studies are accumulating in greater numbers as the technology to determine the genotype at a given locus becomes more accessible. This article discusses the results of both types of studies.
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Affiliation(s)
- Andrea L Sestak
- Department of Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73003, USA.
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30
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Machida H, Tsukamoto K, Wen CY, Shikuwa S, Isomoto H, Mizuta Y, Takeshima F, Murase K, Matsumoto N, Murata I, Kohno S, Wen CY. Crohn’s disease in Japanese is associated with a SNP-haplotype of N-acetyltransferase 2 gene. World J Gastroenterol 2005; 11:4833-7. [PMID: 16097053 PMCID: PMC4398731 DOI: 10.3748/wjg.v11.i31.4833] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the frequency and distribution of N-acetyltransferase 2 (NAT2) and uridine 5’-diphosphate (UDP)-glucuronosyltransferase 1A7 (UGT1A7) genes in patients with ulcerative colitis (UC) and Crohn’s disease (CD).
METHODS: Frequencies and distributions of NAT2 and UGT1A7 SNPs as well as their haplotypes were investigated in 95 patients with UC, 60 patients with CD, and 200 gender-matched, unrelated, healthy, control volunteers by PCR-restriction fragment length polymorphism (RFLP), PCR-denaturing high-performance liquid chromatography (DHPLC), and direct DNA sequencing.
RESULTS: Multiple logistic regression analysis revealed that the frequency of haplotype, NAT2*7B, significantly increased in CD patients, compared to that in controls (P = 0.0130, OR = 2.802, 95%CI = 1.243-6.316). However, there was no association between NAT2 haplotypes and UC, or between any UGT1A7 haplotypes and inflammatory bowel disease (IBD).
CONCLUSION: It is likely that the NAT2 gene is one of the determinants for CD in Japanese. Alternatively, a new CD determinant may exist in the 8p22 region, where NAT2 is located.
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Affiliation(s)
- Haruhisa Machida
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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31
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Zhou S, Chan E, Duan W, Huang M, Chen YZ. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 2005; 37:41-213. [PMID: 15747500 DOI: 10.1081/dmr-200028812] [Citation(s) in RCA: 179] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targets of reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.
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Affiliation(s)
- Shufeng Zhou
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
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Masson LF, Sharp L, Cotton SC, Little J. Cytochrome P-450 1A1 gene polymorphisms and risk of breast cancer: a HuGE review. Am J Epidemiol 2005; 161:901-15. [PMID: 15870154 DOI: 10.1093/aje/kwi121] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cytochrome P-450 (CYP) 1A1 plays a key role in phase I metabolism of polycyclic aromatic hydrocarbons and in estrogen metabolism. It is expressed predominantly in extrahepatic tissues, including the breast. Four CYP1A1 gene polymorphisms (3801T --> C, Ile462Val, 3205T --> C, and Thr461Asp) have been studied in relation to breast cancer. The 3801C variant is more common than the Val variant. Both variants occur more frequently in Asians than in White populations. The 3205T --> C polymorphism has been observed in African Americans only. Little data are available on the geographic/ethnic distribution of the Thr461Asp polymorphism. The functional significance of the polymorphisms is unclear. In 17 studies, no consistent association between breast cancer and CYP1A1 genotype was found. Meta-analysis found no significant risk for the genotypes 1) 3801C/C (relative risk (RR) = 0.97, 95% confidence interval (CI): 0.52, 1.80) or 3801T/C (RR = 0.91, 95% CI: 0.70, 1.19) versus 3801T/T, 2) Val/Val (RR = 1.04, 95% CI: 0.63, 1.74) or Ile/Val (RR = 0.92, 95% CI: 0.76, 1.10) versus Ile/Ile, or 3) Asp/Asp (RR = 0.95, 95% CI: 0.20, 4.49) or Thr/Asp (RR = 1.12, 95% CI: 0.87, 1.43) versus Thr/Thr. Future studies should explore possible interactions between CYP1A1 and sources of polycyclic aromatic hydrocarbons, markers of estrogen exposure, other lifestyle factors influencing hormonal levels, and other genes involved in polycyclic aromatic hydrocarbon metabolism or hormonal biosynthesis.
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Affiliation(s)
- L F Masson
- Epidemiology Group, Department of Public Health, University of Aberdeen, Aberdeen, Scotland.
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Tamer L, Tursen U, Eskandari G, Ates NA, Ercan B, Yildirim H, Atik U. N-acetyltransferase 2 polymorphisms in patients with Behcet's disease. Clin Exp Dermatol 2005; 30:56-60. [PMID: 15663505 DOI: 10.1111/j.1365-2230.2004.01685.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
It is possible that dietary, environmental factors and/or genetic polymorphisms in xenobiotic-metabolizing enzymes may contribute to the development of Behcet's disease. As N-acetyltransferase (NAT) 2 is an important xenobiotic-metabolizing enzyme and theoretically the nonacetylated xenobiotics may induce an autoimmune mechanism, the aim of the present study was to investigate whether the genetic polymorphism of NAT2 plays a role in susceptibility to Behcet's disease. Forty Behcet's disease patients and 82 control subjects were enrolled in the study. NAT2*5A, NAT2*6A, NAT27*A/B and NAT2*14A polymorphisms were detected by using real time PCR with LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). The NAT2*5A and NAT2*6A mutant genotypes carried an increased risk of developing Behcet's disease [odds ratio (OR) = 66.29, 95% confidence interval (CI) = 8.21-535.33; and OR = 24; 95% CI = 2.04-304.98, respectively]. The NAT2*7A/B and NAT2*14A gene polymorphisms were not an increased risk for developing Behcet's disease. As a result of this study we conclude the NAT2 slow acetylator status may be a determinant in susceptibility to Behcet's disease. This finding may have implications for the theories of the pathogenesis of the disease as well as for therapeutic aspects.
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Affiliation(s)
- L Tamer
- Department of Biochemistry, Mersin University, Turkey.
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Skretkowicz K, Skretkowicz J, Gawrońska-Szklarz B, Górnik W, Rychlik-Sych M, Sysa-Jedrzejowska A. Lack of association between arylamine N-acetyltransferase 2 (NAT2) polymorphism and systemic sclerosis. Eur J Clin Pharmacol 2004; 60:773-8. [PMID: 15565348 DOI: 10.1007/s00228-004-0837-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2003] [Accepted: 09/06/2004] [Indexed: 10/26/2022]
Abstract
OBJECTIVES It has been shown that exposure to some environmental toxins may induce scleroderma-like illness in predisposed individuals, but the etiopathogenesis of the idiopathic form of systemic sclerosis (SSc) remains obscure. The genetic background of this illness has been confirmed in multiple studies. We investigated whether patients with SSc differ from healthy subjects with regard to the enzymatic activity of polymorphic N-acetyltransferase 2 (NAT2). METHODS The study was carried out in 39 patients with SSc; 15 fulfilled the criteria of diffuse SSc (dSSc) and 24 of limited SSc (lSSc); an ethnically matched control group consisted of 100 healthy volunteers. Acetylation phenotype was estimated using the isoniazid as a model drug. The most common mutations in the Caucasian population at positions 481T, 803G, 590A and 857A on the NAT2 gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method with deoxyribonucleic acid (DNA) extracted from peripheral blood. RESULTS In the group of patients with SSc, the frequency of fast acetylator genotypes was 38.5% (95% CI 23.4-55.4), while that for the genotypes coding slow acetylator status was 51.3% (95% CI 34.8-67.6). There was a strong correlation between NAT2 phenotype and NAT2 genotype with a concordance of 97%. We did not observe a preponderance of slow acetylators among patients with SSc and in two subsets of SSc. With the sample size analyzed in the present study, there is a 90% probability of detecting significant differences in distribution of slow, fast, and intermediate phenotypes between patients with SSc and controls, there is a difference of at least 30.3, 28.7 and 21.9% in the distribution of these phenotypes in the general population, respectively. CONCLUSION Acetylator status does not seem to be the significant factor in the development of SSc in patients with both subsets of this autoimmune disease, but further studies are required to confirm this conclusion.
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Affiliation(s)
- K Skretkowicz
- Department of Pharmacology and Clinical Pharmacology , Medical University of Lodz, ul. Muszyńskiego 1, 90-151, Lodz, Poland.
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Meyer D, Parkin DP, Seifart HI, Maritz JS, Engelbrecht AH, Werely CJ, van Helden PD. NAT2 slow acetylator function as a risk indicator for age-related cataract formation. PHARMACOGENETICS 2003; 13:285-9. [PMID: 12724621 DOI: 10.1097/00008571-200305000-00008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To show that the slow arylamine N-acetyltransferase type 2 (NAT2) catalysed acetylator function is associated with the development of age-related cataracts. METHODS Both the acetylator phenotype and genotype of 139 patients with age-related cataracts were determined, and the distribution of the acetylator subtypes in the case population was compared with the distribution in the general (control) population. The genotype was determined by restriction-enzyme analysis of DNA, and the phenotype was determined using the elimination characteristics of isoniazid as discriminant. RESULTS The frequency of alleles coding for slow acetylator characteristics was higher in the patients than in the controls, and the difference was significant (P = 0.013). CONCLUSIONS Slow acetylators are at higher risk of developing age-related cataracts than fast acetylators and we suggest that exogenous factors, which can be detoxified by acetylation, are aetiological agents for cataract formation. Identification of and avoidance of such (environmental) agents should reduce the incidence of age-related cataracts.
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Affiliation(s)
- David Meyer
- Department of Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa.
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Yen JH, Chen CJ, Tsai WC, Lin CH, Ou TT, Hu CJ, Liu HW. Manganese superoxide dismutase and cytochrome P450 1A1 genes polymorphisms in rheumatoid arthritis in Taiwan. Hum Immunol 2003; 64:366-73. [PMID: 12590982 DOI: 10.1016/s0198-8859(02)00818-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
To investigate the role of manganese superoxide dismutase (MnSOD) and cytochrome P450 1A1 (CYP1A1) gene polymorphisms in the pathogenesis of rheumatoid arthritis (RA) in Taiwan, MnSOD and CYP1A1 genes polymorphisms were determined by he polymerase chain reaction/restriction fragment length polymorphism method in 112 patients with RA and 96 controls. There were no significant differences in the genotype, allele, and phenotype frequencies of MnSOD Ala-9Val (C1183T) polymorphisms between patients with RA and controls. The polymorphism of MnSOD 5777T, threonine at the 58th amino acid, cannot be found in RA patients and controls in Taiwan. The allele and phenotype frequencies of CYP1A1 4887A and genotype frequency of CYP1A1 4887C/A were lower in RA patients than in controls, whereas the significant difference was lost after correction. MnSOD C1183T polymorphisms were not associated with the clinical manifestations of RA. However, RA patients with CYP1A1 4889G/G have significantly higher frequency of Sjögren's syndrome, especially in the presence of MnSOD 1183T/T. Patients with CYP1A1 4887C/A also have a trend to develop Sjögren's syndrome in the presence of MnSOD 1183T/T. The linkage disequilibrium between CYP1A1 4889G and CYP1A1 6235C can be found in this study. MnSOD gene polymorphisms are not related to susceptibility to RA in Taiwan, whereas individuals with CYP1A1 4887A tend to avoid the development of RA. Moreover, CYP1A1 4889G/G and 4887C/A may play a role in the development of Sjögren's syndrome, especially in the presence of MnSOD 1183T/T. These findings are preliminary. A further confirmation study is necessary.
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Affiliation(s)
- Jeng-Hsien Yen
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan.
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Zschieschang P, Hiepe F, Gromnica-Ihle E, Roots I, Cascorbi I. Lack of association between arylamine N-acetyltransferase 2 (NAT2) polymorphism and systemic lupus erythematosus. PHARMACOGENETICS 2002; 12:559-63. [PMID: 12360107 DOI: 10.1097/00008571-200210000-00008] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The slow arylamine -acetyltransferase 2 (NAT2) phenotype frequently has been assumed to be associated with an elevated risk to develop a lupus-like syndrome after administration of drugs such as procainamide or hydralazine. Moreover, there are conflicting data on the role of acetylator phenotype as a susceptibility factor for systemic lupus erythematosus (SLE). Because most investigations have previously been conducted with relatively small sample sizes, the present study was performed to clarify the possible association between genotypes and SLE among a large European cohort. In a case-control study, 209 patients with SLE (194 women, 15 men) were enrolled and matched by gender to 209 controls without clinical signs of inflammatory diseases. All SLE patients fulfilled at least four of the revised American College of Rheumatology classification criteria of SLE. was genotyped for seven known mutations by polymerase chain reaction/restriction fragment length polymorphism. The frequency of slow acetylation genotypes in SLE patients (59.8%) did not differ significantly from controls (56.5%). The adjusted odds ratio (OR) was 0.95 (95% confidence interval, 0.59-1.53). Further differentiation to gender, cigarette consumption, allergic disorders and specific SLE manifestations revealed an equal distribution of genotypes in all subgroups. We conclude that this large genotyping study in a Caucasian population demonstrated a lack of evidence for an association of the slow acetylator genotype with SLE.
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Affiliation(s)
- Petra Zschieschang
- Institute of Clinical Pharmacology, Department of Medicine, Rheumatology and Clinical Immunology, University Medical Center Charité, Humboldt University of Berlin, Rheumaklinik Buch, Berlin, Germany
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Abstract
Arylamine N-acetyltransferases (NATs) play an important role in the interaction of competing metabolic pathways determining the fate of and response to xenobiotics as therapeutic drugs, occupational chemicals and carcinogenic substances. Individual susceptibility for drug response and possible adverse drug reactions are modulated by the genetic predisposition (manifested for example, by polymorphisms) and the phenotype of these enzymes. For all drugs metabolized by NATs, the impact of different in vivo enzyme activities is reviewed with regard to therapeutic use, prevention of side effects and possible indications for risk assessment by phenotyping and/or genotyping. As genes of NATs are susceptibility genes for multifactorial adverse effects and xenobiotic-related diseases, risk prediction can only be made possible by taking the complexity of events into consideration.
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Affiliation(s)
- Peter Meisel
- Department of Pharmacology, Ernst Moritz Arndt University Greifswald, F-Loeffler-Str. 23d, D-17487 Greifswald, Germany.
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