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Aali F, Barjui SP, Aali F, Reiisi S, Chaleshtori MH, Salehi A. Investigation of the association between (CCTTT)n polymorphism in NOS2 gene and serum IgE level in patients with vernal keratoconjunctivitis in Chaharmahal va Bakhtiari Province. GENE REPORTS 2018. [DOI: 10.1016/j.genrep.2018.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Association evidence of CCTTT repeat polymorphism in the iNOS promoter and the risk of atrial fibrillation in Taiwanese. Sci Rep 2017; 7:42388. [PMID: 28205526 PMCID: PMC5304328 DOI: 10.1038/srep42388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 01/09/2017] [Indexed: 11/17/2022] Open
Abstract
Inducible nitric oxide synthase (iNOS) plays an important role in the pathogenesis of atrial fibrillation (AF). The iNOS promoter has a CCTTT-repeat length polymorphism that can determine the level of gene transcription. This study enrolled 200 AF patients and 240 controls. The length of CCTTT-repeat polymorphism in the iNOS promoter region was examined by polymerase chain reactions, with the alleles with ≤11 repeats designated as S and alleles with ≥12 repeats designated as L alleles. AF patients carried significantly higher frequencies of the LL genotype than control subjects (40.0% versus 28.3%, P = 0.010). Multivariate analysis showed that the presence of LL genotype was significantly associated with AF (odds ratio: 1.87, 95% CI = 1.10–3.17, P = 0.021). In vitro, transient transfection assay in HL-1 atrial myocytes showed that the responsiveness of iNOS transcriptional activity to tachypacing was correlated with the length of the CCTTT-repeats. Right atrial tissues from patients with chronic AF were investigated with immunoconfocal microscopy. Patients with LL genotype exhibited greater oxidative stress and substrate remodeling in their atria than those with non-LL genotypes. Our results suggest that the iNOS microsatellite polymorphism may contribute to the genetic background of AF in Chinese-Taiwanese patients.
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Sowjanya AP, Rao M, Vedantham H, Kalpana B, Poli UR, Marks MA, Sujatha M. Correlation of plasma nitrite/nitrate levels and inducible nitric oxide gene expression among women with cervical abnormalities and cancer. Nitric Oxide 2015; 52:21-8. [PMID: 26435258 DOI: 10.1016/j.niox.2015.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Revised: 08/17/2015] [Accepted: 09/18/2015] [Indexed: 01/10/2023]
Abstract
Cervical cancer is caused by infection with high risk human papillomavirus (HR-HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, -1026T > G (rs2779249) and a novel variant -1153T > A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer.
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Affiliation(s)
- A Pavani Sowjanya
- Institute of Genetics and Hospital for Genetic Diseases, Begumpet, Telangana State, India.
| | - Meera Rao
- Sir Ronald Ross Institute of Tropical and Communicable Diseases, Nallakunta, Hyderabad, Telangana State, India.
| | - Haripriya Vedantham
- Mediciti Institute of Medical Sciences (MIMS) Campus, Ghanpur Village, Medchal Mandal, Ranga Reddy District, 501401 Telangana State, India.
| | - Basany Kalpana
- Mediciti Institute of Medical Sciences (MIMS) Campus, Ghanpur Village, Medchal Mandal, Ranga Reddy District, 501401 Telangana State, India.
| | - Usha Rani Poli
- MNJ Institute of Oncology & Regional Cancer Centre, Lakdikapool, Hyderabad, 500004 Telangana State, India.
| | | | - M Sujatha
- Institute of Genetics and Hospital for Genetic Diseases, Begumpet, Telangana State, India.
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Jiao J, Wu J, Huang D, Liu L. Lack of association of the iNOS gene polymorphism with risk of cancer: a systematic review and Meta-Analysis. Sci Rep 2015; 5:9889. [PMID: 26391304 PMCID: PMC4585729 DOI: 10.1038/srep09889] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 03/19/2015] [Indexed: 12/20/2022] Open
Abstract
In order to investigate the association between the iNOS gene polymorphisms and susceptibility to cancer, a search of English papers was done using Pubmed, the Cochrane Library, Embase, ISI Web of Science, Google (scholar) database, and all Chinese reports were conducted using CBMDisc, Chongqing VIP database, and CNKI database. A total of eight studies were included in this meta-analysis including 1,920 cases and 2,373 controls. The results indicated that the polymorphisms in iNOS gene (C150T(Ser(608) Leu) polymorphism and polymorphic (CCTTT)n repeats) had no association with cancer risk for all genetic models. This meta-analysis suggested that the polymorphisms in the iNOS gene were not associated with cancer risk.
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Affiliation(s)
- Jinghua Jiao
- Department of Anesthesiology, Central Hospital, Shenyang Medical College. Shenyang, 110024, China
| | - Jingyang Wu
- Department of Ophthalmology, The First Affiliated Hospital, China Medical University. Shenyang, 110001, China
| | - Desheng Huang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110001, China
| | - Lei Liu
- Department of Ophthalmology, The First Affiliated Hospital, China Medical University. Shenyang, 110001, China.,Department of Epidemiology, School of Public Health, China Medical University, Shenyang, 110001, China
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Chang YC, Wu WM, Huang YH, Chung WH, Tsai HY, Hsu LA. The (CCTTT) n pentanucleotide repeat polymorphism in the inducible nitric oxide synthase gene promoter and the risk of psoriasis in Taiwanese. Arch Dermatol Res 2015; 307:425-32. [PMID: 25663087 DOI: 10.1007/s00403-015-1542-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/04/2015] [Accepted: 01/16/2015] [Indexed: 11/30/2022]
Abstract
Recently, genome-wide association studies identified a novel psoriasis susceptibility locus tagged by two single-nucleotide polymorphisms (SNPs) rs4795067 and rs28998802, both of which are in the intronic region of inducible nitric oxide synthase (iNOS) gene. This study aimed to assess the role of (CCTTT) n pentanucleotide repeat polymorphisms in the promoter region of iNOS gene in Chinese-Taiwanese patients with psoriasis. In total, 280 patients with psoriasis and 512 control subjects were analyzed for the presence of the iNOS microsatellite polymorphism by polymerase chain reactions. The alleles were classified as S and L alleles according to the number of (CCTTT) n repeats, with the alleles with ≤13 repeats designated as S and alleles with ≥14 repeats designated as L alleles. The distribution of allele frequencies and genotypes was significantly different between the control and psoriasis groups (P = 0.040, and 0.014, respectively). After adjustment for age, sex, body mass index, smoking, diabetes, and hypertension, carriers of the LL genotype were 0.38 (95% confidence interval 0.16-0.95) times less likely than non-carriers to have psoriasis (P = 0.038). The promoter assays demonstrated that the iNOS promoter activity increases in parallel with the repeat number of (CCTTT) n in HaCaT cells. Approximately 70% of the study subjects were genotyped for rs4795067 and rs28998802. The rs4795067 is in linkage disequilibrium with the microsatellite L/S allelic classification. The association of iNOS microsatellite with psoriasis is independent of these known iNOS variants. Our results suggest that the iNOS microsatellite may contribute to the genetic background of psoriasis in Chinese-Taiwanese patients.
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Affiliation(s)
- Ya-Ching Chang
- Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Baloira Villar A, Pousada Fernández G, Vilariño Pombo C, Núñez Fernández M, Cifrián Martínez J, Valverde Pérez D. CCTTT Pentanucleotide Repeats in Inducible Nitric Oxide Synthase Gene Expression in Patients With Pulmonary Arterial Hypertension. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.arbr.2014.03.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Baloira Villar A, Pousada Fernández G, Vilariño Pombo C, Núñez Fernández M, Cifrián Martínez J, Valverde Pérez D. CCTTT pentanucleotide repeats in inducible nitric oxide synthase gene expression in patients with pulmonary arterial hypertension. Arch Bronconeumol 2014; 50:141-5. [PMID: 24439467 DOI: 10.1016/j.arbres.2013.10.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 10/15/2013] [Accepted: 10/16/2013] [Indexed: 11/16/2022]
Abstract
INTRODUCTION One of the pathways involved in pulmonary arterial hypertension (PAH) is the nitric oxide (NO) pathway. A polymorphism in the inducible NO synthase (NOS2) gene has been described, consisting of the CCTTT pentanucleotide repeat, which causes a reduction in NO production. The aim of this study was to determine if this polymorphism increases susceptibility to developing PAH. METHODS Sixty four patients with a diagnosis of PAH groupsi and iv and 50 healthy controls were compared. DNA genotyping of the samples for this polymorphism was performed using PCR. The distribution between both groups was compared and correlated with clinical and haemodynamic parameters and therapeutic response. RESULTS A significantly different distribution was observed in the number of repeats between patients and controls (P<.0001). When the samples were categorised by short forms (both alleles with less than 12repeats) and long forms (≥12 repeats), it was observed that the former had an almost 4-fold risk of developing PAH (odds ratio: 3.83; 95%CI: 1.19-12.32, P=.024). There were no differences between the most common types of PAH, either in therapeutic response or survival. There was no correlation between haemodynamic parameters and the number of repeats in the patients, and only a weak correlation with systolic PAH. CONCLUSIONS There are significant differences in the distribution of the NOS2 promotor CCTTT polymorphism between patients with PAH and the healthy population. A minor CCTTT pentanucleotide repeat in the NOS2 gene may increase the risk of developing PAH.
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Affiliation(s)
| | - Guillermo Pousada Fernández
- Departamento de Bioquímica, Genética e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Pontevedra, España
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The influence of gene-gene and gene-environment interactions on the risk of asbestosis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:405743. [PMID: 23984360 PMCID: PMC3741909 DOI: 10.1155/2013/405743] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 07/03/2013] [Accepted: 07/03/2013] [Indexed: 11/25/2022]
Abstract
This study investigated the influence of gene-gene and gene-environment interactions on the risk of developing asbestosis. The study comprised 262 cases with asbestosis and 265 controls with no asbestos-related disease previously studied for MnSOD, ECSOD, CAT, GSTT1, GSTM1, GSTP1, and iNOS polymorphisms. Data on cumulative asbestos and smoking were available for all subjects. To assess gene-gene and gene-environmental interactions, logistic regression was used. The associations between MnSOD Ala −9Val polymorphism and the risk of asbestosis and between iNOS genotypes and asbestosis were modified by CAT –262 C > T polymorphism (P = 0.038; P = 0.031). A strong interaction was found between GSTM1-null polymorphism and smoking (P = 0.007), iNOS (CCTTT)n polymorphism and smoking (P = 0.054), and between iNOS (CCTTT)n polymorphism and cumulative asbestos exposure (P = 0.037). The findings of this study suggest that the interactions between different genotypes, genotypes and smoking, and between genotypes and asbestos exposure have an important influence on the development of asbestosis and should be seriously considered in future research on occupational/environmental asbestos-related diseases.
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Inducible nitric oxide synthase genetic polymorphism and risk of asbestosis. J Biomed Biotechnol 2011; 2011:685870. [PMID: 21660141 PMCID: PMC3110331 DOI: 10.1155/2011/685870] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Revised: 03/10/2011] [Accepted: 03/23/2011] [Indexed: 11/21/2022] Open
Abstract
Asbestos, a known occupational pollutant, may upregulate the activity of inducible nitric oxide synthase (iNOS) and thus the production of nitric oxide (NO). This study investigated whether iNOS (CCTTT)n polymorphism is associated with an increased asbestosis risk in exposed workers.
The study cohort consisted of 262 cases with asbestosis and 265 controls with no asbestos-related disease. For each subject the cumulative asbestos exposure data were available. The number of CCTTT repeats was determined following PCR amplification of the iNOS promoter region. Logistic regression was performed to estimate asbestosis risk.
The OR of asbestosis was 1.20 (95% CI = 0.85–1.69) for the LL genotype compared to the combined SL and SS genotypes and 1.26 (95% CI = 0.86–1.85) for the LL genotype compared to the SL genotype.
The results of this study are borderline significant and suggest a possible role of iNOS (CCTTT)n polymorphism in the risk of asbestosis; however, further studies are needed.
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Gemayel R, Vinces MD, Legendre M, Verstrepen KJ. Variable tandem repeats accelerate evolution of coding and regulatory sequences. Annu Rev Genet 2011; 44:445-77. [PMID: 20809801 DOI: 10.1146/annurev-genet-072610-155046] [Citation(s) in RCA: 421] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Genotype-to-phenotype mapping commonly focuses on two major classes of mutations: single nucleotide polymorphisms (SNPs) and copy number variation (CNV). Here, we discuss an underestimated third class of genotypic variation: changes in microsatellite and minisatellite repeats. Such tandem repeats (TRs) are ubiquitous, unstable genomic elements that have historically been designated as nonfunctional "junk DNA" and are therefore mostly ignored in comparative genomics. However, as many as 10% to 20% of eukaryotic genes and promoters contain an unstable repeat tract. Mutations in these repeats often have fascinating phenotypic consequences. For example, changes in unstable repeats located in or near human genes can lead to neurodegenerative diseases such as Huntington disease. Apart from their role in disease, variable repeats also confer useful phenotypic variability, including cell surface variability, plasticity in skeletal morphology, and tuning of the circadian rhythm. As such, TRs combine characteristics of genetic and epigenetic changes that may facilitate organismal evolvability.
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Affiliation(s)
- Rita Gemayel
- Laboratory for Systems Biology, VIB, B-3001 Heverlee, Belgium
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Jia S, Ni J, Chen S, Jiang Y, Dong W, Gao Y. Association of the pentanucleotide repeat polymorphism in NOS2 promoter region with susceptibility to migraine in a Chinese population. DNA Cell Biol 2010; 30:117-22. [PMID: 20874490 DOI: 10.1089/dna.2010.1102] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Genes involved in the production of nitric oxide (NO) have been suggested as genetic factors for migraine. It has been studied whether polymorphisms in the genes encoding for different types of NO synthase (NOS) could be involved in the liability to migraine; however, most studies yield negative results. The pentanucleotide repeat microsatellite in the promoter region of inducible NOS (NOS2) shows highly significant differences in allelic frequencies among ethnically diverse populations. Thus, variation in the number of pentanucleotide repeats may have some significance in the predisposition to migraine among different human populations. The aim of this study was to investigate the possible association between pentanucleotide repeat polymorphism and the risk for migraine in Chinese population. We studied the genotypic and allelic frequencies of the pentanucleotide repeat polymorphism in the promoter region of NOS2 in 504 patients with migraine and 512 healthy controls, using polymerase chain reaction amplification and polyacrylamide gel electrophoresis analyses. Comparison of global allele counts between patients and controls showed that the difference was significant (p = 0.0014). The carriage of 9-repeat and 10-repeat alleles was significantly more common in controls, whereas 11-repeat allele was more common in patients after Bonferroni correction for multiple comparisons. A specific analysis of the different cutoffs for number of repeats showed that allelic and genotypic frequencies for the 9-repeat and 10-repeat cutoff were significantly different between cases and controls (p = 0.007 and p = 0.005 for allelic frequencies, respectively; p = 0.0086 and p = 0.0033 for genotypic frequencies, respectively). Our results implied an association between NOS2 pentanucleotide repeat polymorphism and migraine susceptibility in a Chinese population. Considering the significant allelic frequency differences in ethnically diverse populations, further replication studies, especially in ethnically different groups, were necessary to fully establish the role of NOS2 polymorphism in migraine susceptibility.
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Affiliation(s)
- Shasha Jia
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, Jiangsu, PR China
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Ryk C, Steineck G, Wiklund NP, Nyberg T, de Verdier PJ. The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis. J Urol 2010; 184:2150-7. [PMID: 20850837 DOI: 10.1016/j.juro.2010.06.091] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Indexed: 01/22/2023]
Abstract
PURPOSE We analyzed whether the NOS2 promoter microsatellite (CCTTT)n polymorphism influences bladder cancer pathogenesis. MATERIALS AND METHODS We genotyped 359 patients with bladder cancer in a population based cohort and 164 population controls by DNA fragment analysis and sequencing. Genotypes were combined with information on tumor stage, grade and stage, grade progression and cancer specific death. Clinical followup was 5 years. RESULTS We divided (CCTTT)n alleles into short-10 or fewer, intermediate-11 or 12 and long-13 or greater repeats. Patients homozygous for 13 or longer (CCTTT)n repeats were at decreased odds ratio for bladder cancer (p = 0.010). However, after illness developed they were at 3-fold increased hazard ratio for stage progression (p = 0.062) and 4-fold increased hazard ratio for death from bladder cancer (p = 0.056). We discovered what is to our knowledge a previously undescribed polymorphism at position 23105343 (C/T). There was no difference in frequency between bladder cancer cases and population controls for this polymorphism. No associations were found between tumor stage, grade or stage and grade progression. However, patients with bladder cancer with the heterozygous CT genotype were at 3-fold increased hazard ratio of death from cancer (p = 0.011). CONCLUSIONS Nitric oxide can induce proliferation or apoptosis depending on the cellular context. Results suggest that the (CCTTT)n NOS2 microsatellite may influence bladder cancer risk and aggressiveness. This polymorphism may have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.
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Affiliation(s)
- Charlotta Ryk
- Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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Bagarolli RA, Saad MJA, Saad STO. Toll-like receptor 4 and inducible nitric oxide synthase gene polymorphisms are associated with Type 2 diabetes. J Diabetes Complications 2010; 24:192-8. [PMID: 19395279 DOI: 10.1016/j.jdiacomp.2009.03.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 02/07/2009] [Accepted: 03/20/2009] [Indexed: 01/21/2023]
Abstract
BACKGROUND The toll-like receptor 4 (TLR4) and inducible nitric oxide synthase are proteins from the innate immune system that, when activated, can induce insulin resistance. Polymorphisms in these genes, TLR4 and NOS2, respectively, could affect the immune response, as well as the prevalence of Type 2 diabetes (T2DM). OBJECTIVE The aim of the present study was to investigate the contribution of four polymorphisms (two from TLR4 and two from NOS2) to susceptibility to T2DM in a southeast Brazilian population. DESIGN A total of 211 patients with T2DM and 200 unrelated controls were genotyped for the Asp299Gly and Thr399Ile polymorphisms of the TLR4 gene and for the insertion (I)/deletion (D) AAAT and (CCTTT)n polymorphisms of the NOS2 promoter gene. RESULTS With regard to the NOS2 promoter region, the data showed that the I allele of the I/D AAAT polymorphism was more prevalent in the T2DM group and that the L/L genotype of the (CCTTT)n polymorphism was also more frequent in the same group. In contrast, the 299Gly allele and the 399Ile allele from the Asp299Gly and Thr399Ile TLR4 gene polymorphisms, respectively, were associated with protection of T2DM. It is believed that the persistence of these genetic variations in human populations may be indicative of a selective advantage in the face of different environmental pressures. CONCLUSIONS Genetic variations in the NOS2 gene promoter and TLR4 coding sequence may lead to deleterious and protective effects, respectively, arising from altered function of the innate immune system in patients with T2DM.
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Affiliation(s)
- Renata A Bagarolli
- Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil
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Levesque MC, Hobbs MR, O'Loughlin CW, Chancellor JA, Chen Y, Tkachuk AN, Booth J, Patch KB, Allgood S, Pole AR, Fernandez CA, Mwaikambo ED, Mutabingwa TK, Fried M, Sorensen B, Duffy PE, Granger DL, Anstey NM, Weinberg JB. Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. Hum Genet 2009; 127:163-82. [PMID: 19859740 DOI: 10.1007/s00439-009-0753-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2009] [Accepted: 10/05/2009] [Indexed: 10/20/2022]
Abstract
Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.
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Motallebipour M, Rada-Iglesias A, Westin G, Wadelius C. Two polypyrimidine tracts in the nitric oxide synthase 2 gene: similar regulatory sequences with different properties. Mol Biol Rep 2009; 37:2021-30. [PMID: 19669598 DOI: 10.1007/s11033-009-9653-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2009] [Accepted: 07/21/2009] [Indexed: 11/24/2022]
Abstract
We reported previously that the polymorphic polypyrimidine CCTTT-microsatellite in the regulatory region of nitric oxide synthase 2 (NOS2) bound nuclear proteins in vitro. In the present work, we aimed to characterize and investigate a potential regulatory role of the CCTTT-microsatellite in NOS2 expression. Therefore, we performed gel-shift, S1-nuclease, and chromatin immunoprecipitation (ChIP) assays. In vitro experiments showed that the microsatellite formed triplex-DNA both with and without superhelical constraint. We also found that the CCTTT-microsatellite and an apparently similar CT-repeat in the first intron of NOS2 were specifically cleaved by S1-nuclease, when cloned into a supercoiled plasmid. In vitro data suggested that the CCTTT-microsatellite bound both polypyrimidine tract-binding protein (PTBP1) and heterogeneous nuclear ribonucleoprotein K (hnRNPK). On the contrary, ChIP revealed binding of PTBP1 and hnRNPK rather to the CT-repeat in the first intron than to the CCTTT-microsatellite. Enrichment for RNA polymerase II and acetylated histones H3 and H4 was also detected at the intronic site. We suggest that both PTBP1 and hnRNPK binds the single strand of the triplex-DNA formed at the CT-repeat in the first intron and that this interaction could be involved in the regulation of NOS2 expression.
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Affiliation(s)
- Mehdi Motallebipour
- Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden
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Shazia A, Nithya P, Seshadri M. Genetic variation of polymorphic NOS STR locus in ten Indian population groups. RUSS J GENET+ 2009. [DOI: 10.1134/s1022795409020161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Dhangadamajhi G, Mohapatra BN, Kar SK, Ranjit MR. The CCTTT pentanucleotide microsatellite in iNOS promoter influences the clinical outcome in P. falciparum infection. Parasitol Res 2009; 104:1315-20. [PMID: 19153766 DOI: 10.1007/s00436-009-1329-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2008] [Accepted: 01/05/2009] [Indexed: 11/25/2022]
Abstract
To assess the hypothesis that nitric oxide (NO) is critical in the pathogenesis of cerebral malaria, we analyzed those single nucleotide polymorphisms (SNPs) and microsatellite (MS) of the promoter region of inducible nitric oxide synthase (iNOS) gene which are known to enhance the NO production in vivo. A total of 428 (204 severe, 224 mild) adult patients living in the eastern part of India were analyzed. The single nucleotide substitutions -954G-->C was found to be very rare, and -1173C-->T was absent in this population. But interestingly, longer forms of MS were found to be significantly associated with severe malaria (OR = 2.89, 95% CI = 1.955-4.295, P < 0.0001), and the linear regression analysis revealed that the risk of severe malaria significantly increases as the summed repeat number in an individual increase (OR = 1.16, P = 0.0013). Further, the median plasma level of nitrate/nitrite (NOx) was observed to be high in mild patients compared to severe patients, and the level of parasitemia was significantly low among mild patients than severe ones. These findings suggest that the CCTTT repeats in iNOS may play a key role in the pathogenesis of severe malaria.
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Affiliation(s)
- G Dhangadamajhi
- Regional Medical Research Centre (ICMR), Bhubaneswar, Orissa, India
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Ahmad S, Ghosh A, Nair DL, Seshadri M. Simultaneous extraction of nuclear and mitochondrial DNA from human blood. Genes Genet Syst 2008; 82:429-32. [PMID: 17991998 DOI: 10.1266/ggs.82.429] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
A method of simultaneous isolation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) from human blood has been proposed by improvising Lahiri's method of isolation of nuclear DNA. The approach presented here provides selectively enriched fractions and eliminates the need for two different methods or separate reagent sets for the extraction of nDNA and mtDNA. It employs an initial nuclear/ cytoplasm partitioning, followed by the similar procedural steps for the two fractions separately. It gives good quality and quantity of the nDNA as well as the mtDNA, suitable for processes like PCR amplification and sequencing and may prove to be useful for people studying population genetics and evolution using molecular markers maximizing the available resources, especially in cases where a large database needs to be generated from limited amount of blood sample. From 3 ml of blood, the yields of mtDNA salvaged from the supernatant were sufficient to set approximately 4x10(5) reactions (starting with 250 fg DNA per reactions) of mtDNA loci which otherwise would have been discarded as per original Lahiri's procedure. The quality of mtDNA from the mitochondrial fraction was suitable for all major downstream processes as confirmed by locus specific PCR amplifications and sequencing. Through this procedure, the wastage of nDNA can be avoided when mtDNA loci is studied.
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Affiliation(s)
- Shazia Ahmad
- Low Level Radiation Studies Section, Radiation Biology and Health Science Division, Bio-Medical Group, Bhabha Atomic Research Center, Mumbai, India.
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Holla LI, Stejskalova A, Znojil V, Vasku A. Analysis of the inducible nitric oxide synthase gene polymorphisms in Czech patients with atopic diseases. Clin Exp Allergy 2007; 36:1592-601. [PMID: 17177683 DOI: 10.1111/j.1365-2222.2006.02612.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Nitric oxide (NO) is an important mediator of physiologic processes in the airways; it plays a significant role in the regulation of the T helper type 1/type 2 balance and contributes to the development of atopic diseases. OBJECTIVE We analysed several polymorphisms mainly in the promoter region of the inducible NO synthase (NOS2, iNOS) gene and investigated their associations with asthma and/or atopic phenotypes. METHODS We performed a case-control study in 994 subjects (661 patients with atopic disorders, with subgroups of 304 patients with allergic asthma, and 333 healthy individuals), matched for sex, living in the same geographical area. Screening for polymorphisms was performed by combination of PCR and direct sequencing analysis. RESULTS We analysed 14 nucleotide sequence variants, seven most common of which were typed in quite large groups of our asthmatic, atopic and control populations. None of these seven frequent polymorphisms was associated with the phenotype bronchial asthma or other atopic diseases. Nevertheless, three from six common promoter polymorphisms showed a significant relation to feather's positivity (P value from 0.01 to 0.03) and the NOS2 608Leu variant was significantly associated with asthma severity [p(corr) = 0.0005; odds ratio (OR) = 5.00, 95% confidence interval (CI): 1.88-13.33]. In haplotype analysis, the most common -2447C/-1659C/-1026G/-0.7del/-277A/Ser608 haplotype was associated with a lower risk of asthma when compared with the common haplotypes with frequency more than 5% (P = 0.01, p(corr) < 0.05; OR = 0.65, 95% CI: 0.56-0.77). CONCLUSION Our findings suggest that inducible NOS can play a role in atopic disorders, and several polymorphisms in its gene may be important for asthma protection or susceptibility.
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Affiliation(s)
- L I Holla
- Department of Pathophysiology, Medical Faculty, Masaryk University Brno, Brno, Czech Republic
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Gómez LM, Anaya JM, Vilchez JR, Cadena J, Hinojosa R, Vélez L, Lopez-Nevot MA, Martín J. A polymorphism in the inducible nitric oxide synthase gene is associated with tuberculosis. Tuberculosis (Edinb) 2007; 87:288-94. [PMID: 17475563 DOI: 10.1016/j.tube.2007.03.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2006] [Revised: 03/03/2007] [Accepted: 03/03/2007] [Indexed: 12/24/2022]
Abstract
iNOS or NOS2 is a molecule that plays a key role in the immunological control of a broad spectrum of infectious agents. Investigation is hampered by difficulty in estimating in vivo production of nitric oxide (NO), but genetic studies provide a potential means of examining the relation between NO production and disease outcome. To better characterize the host genetic factors determining the susceptibility to TB, we evaluated the influence of two polymorphisms in the NOS2A gene on the risk of developing pulmonary TB in a Northwestern Colombian population, which is a moderately-high endemic area. One hundred and fourteen patients with TB and negative for human immunodeficiency virus, plus 304 healthy controls were examined for NOS2A CCTTT and TAAA polymorphisms. A total of 160 healthy controls mentioned before, underwent tuberculin skin test (TST). Analysis disclosed significant differences between patients and controls with NOS2A CCTTT polymorphism (P=0.0001, Pc=0.001, OR=0.4, and 95%CI=0.3-0.7) independent of TST status. When the NOS2A alleles were stratified into short (8-11) and long (12-16) repeats, significant differences with short repeats were observed between TB patients and all controls (P=0.005, OR=0.63, 95%CI=0.46-0.86). No individual association with NOS2A TAAA was detected. These results indicate that a polymorphism in the NOS2A gene influences the susceptibility to TB and suggest a role for NOS2A in the pathogenesis of mycobacterial infection.
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Affiliation(s)
- Luis Miguel Gómez
- Cellular Biology and Immunogenetics Unit, Corporación para Investigaciones Biológicas (CIB), Cra. 72-A, No. 78-B-141, Medellín, Colombia
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21
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Shen CH, Wang YH, Wang WC, Jou YC, Hsu HS, Hsieh HY, Chiou HY. Inducible nitric oxide synthase promoter polymorphism, cigarette smoking, and urothelial carcinoma risk. Urology 2007; 69:1001-1006. [PMID: 17482959 DOI: 10.1016/j.urology.2007.02.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2006] [Revised: 01/08/2007] [Accepted: 02/16/2007] [Indexed: 11/18/2022]
Abstract
OBJECTIVES Bladder carcinoma has a high inducible nitric oxide synthase (iNOS) content, and a highly polymorphic (CCTTT)n repeat in the iNOS promoter region has been identified. We explored whether this iNOS promoter polymorphism and cigarette smoking are associated with urothelial carcinoma (UC) risk. METHODS A total of 250 patients with pathologically confirmed UC and 250 unrelated noncancer controls were serially recruited at the Chia Yi Christian Hospital from August 2002 to May 2005. Multivariate logistic regression analysis was used to calculate the odds ratio and 95% confidence interval (CI). RESULTS A significantly increased UC risk was found in those who had smoked more than 30 years (odds ratio 2.4, 95% CI 1.5 to 4.2). The study subjects carrying the 12-repeat allele had a significantly increased UC risk (odds ratio 1.7, 95% CI 1.1 to 2.5). We also found the investigated polymorphism was related to clinical stage (P = 0.043). Of those who had ever smoked, those with the short/long (S/L) and long/long (L/L) genotypes (S, 9 to 11 repeats; L, 12 to 18 repeats) and the 12-repeat allele had a significantly increased UC risk of 3.5 (95% CI 1.7 to 7.3) and 4.5 (95% CI 2.2 to 8.9), respectively. Of the study subjects who had smoked longer than 30 years, those with S/L and L/L genotypes and the 12-repeat allele had significantly increased UC risks of 2.4 (95% CI 1.3 to 4.7) and 3.8 (95% CI 1.8 to 8.0), respectively. CONCLUSIONS These findings suggest that the polymorphic (CCTTT)n repeat in the iNOS promoter region might be involved in the development of UC, especially in those who have ever smoked.
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Affiliation(s)
- Cheng-Huang Shen
- Department of Urology, Chia Yi Christian Hospital, Chia Yi City, Taiwan
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22
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Goto Y, Ando T, Naito M, Goto H, Hamajima N. Inducible nitric oxide synthase polymorphism is associated with the increased risk of differentiated gastric cancer in a Japanese population. World J Gastroenterol 2006; 12:6361-5. [PMID: 17072962 PMCID: PMC4088147 DOI: 10.3748/wjg.v12.i39.6361] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [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 examine the association of inducible nitric oxide synthase (iNOS) C150T polymorphism with gastric cancer, as well as with gastric atrophy and H pylori seropositivity.
METHODS: A single nucleotide polymorphism of iNOS C150T was examined for 454 Japanese health checkup examinees (126 males and 328 females) aged 35 to 85 years without a history of cancer and 202 gastric cancer patients (134 males and 68 females) aged 33 to 94 years with pathologically confirmed diagnosis of gastric adenocarcinoma.
RESULTS: The iNOS C150T polymorphism was not associated with gastric atrophy or with H pylori seropositivity. The odds ratio (OR) of the C/T + T/T for gastric cancer was increased without statistical significance (OR=1.19, 95% confidence interval (CI): 0.68-2.08). In the differentiated subgroup (n = 113), however, the OR of the C/T genotype for gastric cancer was significant (OR = 2.02, 95% CI: 1.04-3.92) relative to the C/C genotype. In addition, considering the location of gastric cancer (n = 105), there were significant differences between the controls and non-cardia group with the OR of 2.13 (95% CI: 1.08-4.18) for C/T and 1.94 (95% CI: 1.00-3.78) for C/T + T/T.
CONCLUSION: The iNOS C150T polymorphism is associated with the risk of H pylori-related gastric cancer in a Japanese population. This polymorphism may play an important role in increasing the risk of gastric cancer in Asian countires with the highest rates of gastric cancer.
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Affiliation(s)
- Yasuyuki Goto
- Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya 466-8550, Japan.
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Leung TF, Liu EKH, Li CY, Chan IHS, Yung E, Lam CWK, Wong GWK. Lack of association between NOS2 pentanucleotide repeat polymorphism and asthma phenotypes or exhaled nitric oxide concentration. Pediatr Pulmonol 2006; 41:649-55. [PMID: 16703578 DOI: 10.1002/ppul.20428] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Nitric oxide (NO) plays an immunoregulatory role in balancing cellular immunity. The expression of inducible nitric oxide synthase gene (NOS2) is upregulated upon exposure to proinflammatory cytokines and microbial exposure. The (CCTTT)n polymorphism in NOS2 promoter confers protection against infections and immunological disorders including atopy. We investigated the association between (CCTTT)n and asthma traits in Chinese children. Asthmatic children between 5 and 18 years of age and non-allergic controls were recruited. Plasma total and specific IgEs were measured by immunoassays, and exhaled NO concentration was quantified online by chemiluminescence. NOS2 (CCTTT)n was genotyped by GeneScan analysis. The mean (SD) age of 291 asthmatics and 172 controls were 11.1 (3.8) years and 11.6 (4.0) years, respectively (P = 0.259). NOS2 (CCTTT)n followed Hardy-Weinberg equilibrium in both groups, and its uni-modal allele distribution peaks at 12-repeat. Significant interethnic differences in (CCTTT)n alleles were observed, with our Chinese having less 13-repeat (Pc = 0.022) but more 17-repeat (Pc = 0.033) than Caucasians. The frequency of 14-repeat allele was similar in our Chinese as compared to Japanese (Pc = 0.32). Multivariate regression analyses failed to detect any association between this polymorphic marker and asthma diagnosis (P = 0.949), atopy (P = 0.305), IgE sensitization to aeroallergens (P > 0.2 for all), or FeNO (P = 0.847). These findings do not support NOS2 to be a major candidate gene for asthma or IgE-mediated allergic diseases in Chinese children.
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Affiliation(s)
- Ting F Leung
- Department of Pediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China.
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24
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Cramer JP, Nüssler AK, Ehrhardt S, Burkhardt J, Otchwemah RN, Zanger P, Dietz E, Gellert S, Bienzle U, Mockenhaupt FP. Age-dependent effect of plasma nitric oxide on parasite density in Ghanaian children with severe malaria. Trop Med Int Health 2005; 10:672-680. [PMID: 15960706 DOI: 10.1111/j.1365-3156.2005.01438.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Nitric oxide (NO) has toxic properties against Plasmodium falciparum. While high blood levels have been associated with protection against severe malarial disease, they may also contribute to the pathophysiology of cerebral malaria and severe anaemia. Promoter variants in the inducible nitric oxide synthase (iNOS) gene have been shown to influence NO concentrations and disease manifestation. However, findings are conflicting. We examined associations of plasma NO metabolites (NOx) with symptoms of severe malaria, particularly malarial anaemia and cerebral malaria, and with iNOS promoter variants. In 210 Ghanaian children with severe malaria, we measured plasma nitrite, nitrate, and S-nitrosothiol, and genotyped the iNOS promoter variants -954G-->C, -1173C-->T, and the -2.5 kb (CCTTT)(n) microsatellite. NOx levels decreased with age. In young children (<24 months), high NOx was associated with reduced parasite density. This was not seen in patients of 24-48 months of age and reversed in older children. Subgroup analysis revealed that in children with severe anaemia but without cerebral involvement (prostration, impaired consciousness, convulsions), high NOx levels correlated with low parasitaemia (P = 0.02). In these children, elevated NOx levels were also associated with the iNOS-954C-->T/(CCTTT)(8) haplotype (P = 0.03). No association between NOx or iNOS genotypes and cerebral malaria was observed. Our findings suggest that in young children with severe malaria NOx reduces parasitaemia. This effect wanes at higher ages and may reflect a predominance of unspecific immune responses to infection in early childhood. This finding may have importance for the understanding of associations between iNOS variants and severe malaria in regions of differing disease manifestation.
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Affiliation(s)
- Jakob P Cramer
- Institute of Tropical Medicine Berlin, Charité- University Medicine Berlin, Germany.
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25
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Polymorphic markers of the NO synthase genes and genetic predisposition to diabetic polyneuropathy in type 1 diabetes mellitus. Mol Biol 2005. [DOI: 10.1007/s11008-005-0029-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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26
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Tatemichi M, Sawa T, Gilibert I, Tazawa H, Katoh T, Ohshima H. Increased risk of intestinal type of gastric adenocarcinoma in Japanese women associated with long forms of CCTTT pentanucleotide repeat in the inducible nitric oxide synthase promoter. Cancer Lett 2005; 217:197-202. [PMID: 15617837 DOI: 10.1016/j.canlet.2004.09.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2004] [Revised: 08/31/2004] [Accepted: 09/01/2004] [Indexed: 11/25/2022]
Abstract
Tandem repeat number polymorphism of a CCTTT pentanucleotide in the promoter region of the inducible nitric oxide synthase gene (iNOS) and a polymorphism of the interleukin-1beta (IL-1B) promoter at position -31 were analyzed in DNA samples from 181 Japanese control subjects and 158 gastric cancer patients, including 96 intestinal type and 62 diffuse type. An association between the intestinal type of gastric adenocarcinoma and higher promoter activity of the iNOS gene was found in women, especially those having higher promoter activity of the IL-1B gene and without a history of smoking. Our results imply that chronic inflammation caused by excess nitric oxide generated by iNOS contributes to Helicobacter pylori-induced gastric cancer.
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Affiliation(s)
- Masayuki Tatemichi
- International Agency for Research on Cancer, 150 Cours Albert Thomas, F 69372 Lyon Cedex 08, France
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27
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Cramer JP, Mockenhaupt FP, Ehrhardt S, Burkhardt J, Otchwemah RN, Dietz E, Gellert S, Bienzle U. iNOS promoter variants and severe malaria in Ghanaian children. Trop Med Int Health 2004; 9:1074-80. [PMID: 15482399 DOI: 10.1111/j.1365-3156.2004.01312.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Nitric oxide is an important mediator in the host defence against Plasmodium falciparum malaria. It has antiparasitic effects in vitro. However, its role in clinical disease remains controversial. Polymorphisms in the inducible nitric oxide synthase promoter (iNOS; -954G-->C, -1173C-->T, -2.6 kb CCTTT(n) microsatellite) may influence susceptibility to and severity of malaria. We tested this hypothesis in a case-control study among Ghanaian children with severe malaria (SM) and asymptomatic parasitaemia, respectively, and in healthy controls. In this study, the respective frequencies of iNOS-954G-->C and -1173C-->T did not differ between groups but > or =13 microsatellite copies were associated with SM. -954G-->C and -1173C-->T were in linkage disequilibrium with CCTTT(8) and CCTTT(13), respectively. -954G-->C/CCTTT(8) protected against hyperparasitaemia whereas -1173C-->T/CCTTT(13) increased fatality. These findings suggest that iNOS promoter haplotypes rather than single nucleotide polymorphisms are associated with malaria in Ghanaian children.
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Affiliation(s)
- Jakob P Cramer
- Institute of Tropical Medicine, Charité, Humboldt-University, Berlin, Germany.
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28
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Burgner D, Rockett K, Ackerman H, Hull J, Usen S, Pinder M, Kwiatkowski DP. Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations. Genes Immun 2004; 4:506-14. [PMID: 14551604 DOI: 10.1038/sj.gene.6364022] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A(-2.6) microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A(-2.6) microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus- and population-specific LD is essential when designing and interpreting genetic association studies.
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Affiliation(s)
- D Burgner
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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29
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Orozco G, Sánchez E, López-Nevot MA, Caballero A, Bravo MJ, Morata P, de Dios Colmenero J, Alonso A, Martín J. Inducible nitric oxide synthase promoter polymorphism in human brucellosis. Microbes Infect 2004; 5:1165-9. [PMID: 14623011 DOI: 10.1016/j.micinf.2003.08.010] [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: 11/24/2022]
Abstract
Nitric oxide (NO), produced by the inducible nitric oxide synthase (NOS2) protein, is a defence mechanism against various pathogens, including bacteria of the genus Brucella. The aim of this study was to investigate the possible association between the NOS2 gene promoter polymorphism, TAAA(n) and CCTTT(n) microsatellites, and the predisposition to human brucellosis. We performed a case-control study in 85 patients with brucellosis and 100 healthy individuals, matched for age and sex, living in the same geographic area, in whom the NOS2 promoter was genotyped by using a polymerase chain reaction (PCR)-based method combined with fluorescent technology. No statistically significant differences were observed in the distribution of TAAA(n) alleles between the groups under study. When the overall NOS2 CCTTT(n) allele distribution of the brucellosis patients was compared with that of the control subjects, a significant skewing was observed (P = 0.04, by chi(2) test from 2 x 9 contingency table). Interestingly, we observed a trend towards Brucella infection protection with the 9 repeat (181 bp) allele (1.8% patients vs. 7.5% controls; P = 0.01, odds ratios = 0.22, 95% confidence interval = 0.05-0.83), which turned out to be non-significant after applying multiple testing. We concluded that the NOS2 microsatellite polymorphism might not have a major effect on brucellosis; nevertheless, the fact that a non-significant trend towards protection was detected in the CCTTT(n) alleles may be an indication for a follow-up study.
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Affiliation(s)
- Gisela Orozco
- Instituto de Parasitología y Biomedicina López-Neyra, CSIC, C/Ventanilla No 11, 18001 Granada, Spain
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Rovio AT, Abel J, Ahola AL, Andres AM, Bertranpetit J, Blancher A, Bontrop RE, Chemnick LG, Cooke HJ, Cummins JM, Davis HA, Elliott DJ, Fritsche E, Hargreave TB, Hoffman SMG, Jequier AM, Kao SH, Kim HS, Marchington DR, Mehmet D, Otting N, Poulton J, Ryder OA, Schuppe HC, Takenaka O, Wei YH, Wichmann L, Jacobs HT. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Mamm Genome 2004; 15:492-502. [PMID: 15181541 DOI: 10.1007/s00335-004-3049-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2003] [Accepted: 02/01/2004] [Indexed: 10/26/2022]
Abstract
The human nuclear gene for the catalytic subunit of mitochondrial DNA polymerase gamma ( POLG) contains within its coding region a CAG microsatellite encoding a polyglutamine repeat. Previous studies demonstrated an association between length variation at this repeat and male infertility, suggesting a mechanism whereby the prevalent (CAG)(10) allele, which occurs at a frequency of >80% in different populations, could be maintained by selection. Sequence analysis of the POLG CAG microsatellite region of more than 1000 human chromosomes reveals that virtually all allelic variation at the locus is accounted for by length variation of the CAG repeat. Analysis of POLG from African great apes shows that a prevalent length allele is present in each species, although its exact length is species-specific. In common chimpanzee ( Pan troglodytes) a number of different sequence variants contribute to the prevalent length allele, strongly supporting the idea that the length of the POLG microsatellite region, rather than its exact nucleotide or amino acid sequence, is what is maintained. Analysis of POLG in other primates indicates that the repeat has expanded from a shorter, glutamine-rich sequence, present in the common ancestor of Old and New World monkeys.
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Affiliation(s)
- Anja T Rovio
- Institute of Medical Technology and Tampere University Hospital, University of Tampere, FIN-33014, Finland
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Jamieson SE, Miller EN, Black GF, Peacock CS, Cordell HJ, Howson JMM, Shaw MA, Burgner D, Xu W, Lins-Lainson Z, Shaw JJ, Ramos F, Silveira F, Blackwell JM. Evidence for a cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun 2004; 5:46-57. [PMID: 14735149 DOI: 10.1038/sj.gene.6364029] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The region of conserved synteny on mouse chromosome 11/human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.
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Affiliation(s)
- S E Jamieson
- Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK
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Matsuura T, Ashizawa T. Spinocerebellar ataxia type 10: a disease caused by a large ATTCT repeat expansion. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 516:79-97. [PMID: 12611436 DOI: 10.1007/978-1-4615-0117-6_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Tohru Matsuura
- Department of Neurology, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, Texas 77030 USA
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Burgner D, Usen S, Rockett K, Jallow M, Ackerman H, Cervino A, Pinder M, Kwiatkowski DP. Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria. Hum Genet 2003; 112:379-86. [PMID: 12552317 DOI: 10.1007/s00439-002-0882-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2002] [Accepted: 11/05/2002] [Indexed: 11/29/2022]
Abstract
To assess the hypothesis that nitric oxide is critical in the pathogenesis of cerebral malaria, we analysed genetic variation in the proximal promoter region of NOS2A, the gene encoding inducible nitric oxide synthase. Sequencing 72 Gambian chromosomes revealed 11 single nucleotide polymorphisms in 2.5 kB (theta=8.6 x 10(-4)). Genotyping 104 nuclear families identified six common haplotypes. A single haplotype, uniquely defined by the NOS2A-1659T allele, was associated with cerebral malaria by a transmission disequilibrium test of 334 affected children and their parents (P=0.02). An independent case-control study of 505 different children from the same population replicated the allelic association with cerebral malaria (odds ratio: 1.31, P=0.04). Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria. Despite high linkage disequilibrium across the region studied, this association would not have been detected without the initial construction of a dense marker set for haplotype tagging.
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Affiliation(s)
- David Burgner
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX2 7BN, UK
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Khajoee V, Kariyazono H, Ohno T, Ihara K, Mizuno Y, Kusuhara K, Hara T. Inducible and endothelial constitutive nitric oxide synthase gene polymorphisms in Kawasaki disease. Pediatr Int 2003; 45:130-4. [PMID: 12709136 DOI: 10.1046/j.1442-200x.2003.01684.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Nitric oxide (NO) is secreted by immune and vascular endothelial cells, and appears to play important roles in the pathophysiology of Kawasaki disease (KD). Thus, genetic variations in NO synthase (NOS) genes may be involved in the development of coronary artery lesions (CAL) in KD. METHODS The present study investigated the association of endothelial constitutive NOS (ecNOS) and inducible NOS (iNOS) gene polymorphisms with the development of CAL in KD in a Japanese population. RESULTS The genotype distributions of 27-bp tandem repeat polymorphism within intron 4 of ecNOS gene did not show any significant difference between controls and KD patients with or without CAL. In addition, there was no significant association between whole-allele distribution of iNOS gene promoter (penta-repeat CCTTT) polymorphism and KD with or without CAL. CONCLUSION These results did not support any association of ecNOS and iNOS gene polymorphisms to the development of CAL in KD patients in a Japanese population.
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Affiliation(s)
- Vahid Khajoee
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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35
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Sohni YR, Burke JP, Dyck PJ, O'Kane DJ. Microfluidic chip-based method for genotyping microsatellites, VNTRs and insertion/deletion polymorphisms. Clin Biochem 2003; 36:35-40. [PMID: 12554058 DOI: 10.1016/s0009-9120(02)00420-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We have developed a method to genotype variable number of tandem repeats (VNTRs) and insertion/deletion polymorphisms using an integrated microfluidic chip-based system. We used this method to analyze a) a highly polymorphic pentanucleotide repeat (CCTTT)(n) locus within the 5'-putative promoter region of the human inducible nitric oxide synthase gene (iNOS5) which is associated with diabetic complications and infectious diseases; b) a bi-allelic 27 bp VNTR region within intron 4 of endothelial nitric oxide gene (eNOS27) which is associated with hypertension in type 2 diabetes patients with coronary heart disease and excess risk of advanced diabetic nephropathy in type 1 diabetes patients and c) an insertion/deletion polymorphism within the gene encoding angiotensin-converting enzyme (ACE/ID) which is associated with cardiovascular pathology and nitric oxide activity, and is in strong linkage disequilibrium with functional variants. Following amplifications, samples were mixed with gel-dye and markers and loaded into commercially available microfluidic chips designed for DNA sizing applications. In the study (N = 230), 95 (41%) of the DNA samples were homozygous and 135 (59%) were heterozygous for the iNOS5 repeats. For eNOS27, 173 (75%) of the genotyped DNA samples were homozygous for the larger 4b allele and the remaining 57 samples (25%) were heterozygous (4b/4a). No DNA samples were homozygous for the shorter 4a allele with four 27 bp repeats. In case of ACE/ID, 47 (20%) of the DNA samples were homozygous for the insertion, 65 (28%) were homozygous for the deletion and the remaining 118 (51%) were heterozygous. The results obtained were verified by analyzing random amplicons using bi-directional sequencing and GeneScan 3.0 analyses with 100% concordance being observed. Using the microfluidic chip-based method, separation and DNA sizing and genotyping are rapidly accomplished. The DNA fragments are resolved clearly and the system allows quantitation. Finally, the microfluidic chip-based method may be used for both large- and small-scale genotyping studies.
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Affiliation(s)
- Youvraj R Sohni
- Translational Genomics Center, Mayo Clinic, Rochester, MN 55905, USA
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Kleinert H, Schwarz PM, Förstermann U. Regulation of the Expression of Inducible Nitric Oxide Synthase. Biol Chem 2003; 384:1343-64. [PMID: 14669979 DOI: 10.1515/bc.2003.152] [Citation(s) in RCA: 291] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nitric oxide (NO), generated by the inducible isoform of nitric oxide synthase (iNOS), has been described to have beneficial microbicidal, antiviral, antiparasital, immunomodulatory, and antitumoral effects. However, aberrant iNOS induction at the wrong place or at the wrong time has detrimental consequences and seems to be involved in the pathophysiology of several human diseases. iNOS is primarily regulated at the expression level by transcriptional and post-transcriptional mechanisms. iNOS expression can be induced in many cell types with suitable agents such as bacterial lipopolysaccharides (LPS), cytokines, and other compounds. Pathways resulting in the induction of iNOS expression may vary in different cells or different species. Activation of the transcription factors NF-kappaB and STAT-1alpha, and thereby activation of the iNOS promoter, seems to be an essential step for iNOS induction in most cells. However, at least in the human system, also post-transcriptional mechanism are critically involved in the regulation of iNOS expression. The induction of iNOS can be inhibited by a wide variety of immunomodulatory compounds acting at the transcriptional levels and/or post-transcriptionally.
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Affiliation(s)
- Hartmut Kleinert
- Department of Pharmacology, Johannes Gutenberg University, D-55101 Mainz, Germany
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Hobbs MR, Udhayakumar V, Levesque MC, Booth J, Roberts JM, Tkachuk AN, Pole A, Coon H, Kariuki S, Nahlen BL, Mwaikambo ED, Lal AL, Granger DL, Anstey NM, Weinberg JB. A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet 2002; 360:1468-75. [PMID: 12433515 DOI: 10.1016/s0140-6736(02)11474-7] [Citation(s) in RCA: 141] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Nitric oxide (NO) is a mediator of immunity to malaria, and genetic polymorphisms in the promoter of the inducible NO synthase gene (NOS2) could modulate production of NO. We postulated that NOS2 promoter polymorphisms would affect resistance to severe malaria. METHODS We assessed genomic DNA from healthy children and from those diagnosed with malaria from Tanzania (n=47 and n=138, respectively) and Kenya (n=1106) for polymorphisms by single-stranded conformational polymorphism (SSCP) analysis and sequencing. We also measured in-vivo NO production in Tanzanian children. FINDINGS We identified a novel single nucleotide polymorphism, -1173 C-->T, in the NOS2 promoter that was significantly associated with protection from symptomatic malaria (odds ratio 0.12, 95% CI 0.03-0.48, p=0.0006) in 179 Tanzanian children, and significantly associated with protection from severe malarial anaemia (adjusted relative risk 0.25, 95% CI 0.09-0.66, p=0.0005) in 1106 Kenyan children studied over 5 years. The risk of parasitaemia was not significantly different in wild-type or -1173 C-->T individuals. -1173 C-->T protection in Tanzanians was independent of the previously recognised NOS2-954 G-->C polymorphism. The (CCTTT)(n) NOS2 polymorphism (Tanzania and Kenya) was not associated with severe malaria outcomes. -1173 C-->T was associated with increased fasting urine and plasma NO metabolite concentrations in Tanzanian children, suggesting that the polymorphism was functional in vivo. Interpretation The NOS2 promoter -1173 C-->T single nucleotide polymorphism is associated with protection against cerebral malaria and severe malarial anaemia. Increased NO production in individuals with the -1173 C-->T polymorphism lends support to a protective role for NO against these syndromes. Targeted interventions to increase NO delivery or production could provide novel preventive and therapeutic strategies against these major causes of mortality in African children.
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MESH Headings
- Anemia/etiology
- Anemia/immunology
- Child
- Child, Preschool
- Female
- Humans
- Immunity, Innate/genetics
- Infant
- Kenya
- Malaria, Cerebral/immunology
- Malaria, Falciparum/complications
- Malaria, Falciparum/genetics
- Malaria, Falciparum/immunology
- Malaria, Falciparum/metabolism
- Male
- Nitric Oxide/biosynthesis
- Nitric Oxide Synthase/genetics
- Nitric Oxide Synthase Type II
- Parasitemia/immunology
- Polymorphism, Genetic
- Polymorphism, Single-Stranded Conformational
- Sequence Analysis, DNA
- Tanzania
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Affiliation(s)
- Maurine R Hobbs
- Department of Internal Medicine, University of Utah and VA Medical Centers, Salt Lake City, UT, USA
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Sjöstrand C, Modin H, Masterman T, Ekbom K, Waldenlind E, Hillert J. Analysis of nitric oxide synthase genes in cluster headache. Cephalalgia 2002; 22:758-64. [PMID: 12421162 DOI: 10.1046/j.1468-2982.2002.00452.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The aetiology of cluster headache is still not yet completely understood, but the potential relevance of genetic factors has been recognized during recent years. Nitric oxide (NO) plays a critical role in the regulation of vasodilation, neurotransmission, inflammation and many other events throughout the body. NO also appears to be an important mediator of vascular headache pathophysiology. In this study we have performed an association analysis of five polymorphic microsatellite markers in the three different NO synthase (NOS) genes; nNOS (NOS1), iNOS (NOS2A) and eNOS (NOS3). Ninety-one cluster headache patients diagnosed according to International Headache Society criteria and 111 matched controls were studied. Phenotype and allele frequencies were similarly distributed in patients and controls except for an iNOS (NOS2A) pentanucleotide repeat allele which was significantly more common in controls. We observed a higher phenotype frequency of this allele in our control group compared with rates in control groups of other studies, whereas the frequency in our patients was similar to that in controls from previous reports. Thus, we conclude that it is unlikely that genetic variations within the NOS genes contribute greatly to cluster headache susceptibility.
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Affiliation(s)
- C Sjöstrand
- Department of Neurology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.
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Rueda B, López-Nevot MA, Pascual M, Ortega E, Maldonado J, López ML, Koeleman BPC, Martín J. Polymorphism of the inducible nitric oxide synthase gene in celiac disease. Hum Immunol 2002; 63:1062-5. [PMID: 12392860 DOI: 10.1016/s0198-8859(02)00443-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The aim of this study was to investigate the possible association between the inducible nitric oxide synthase (NOS2) gene promoter polymorphism, CCTTTn microsatellite, with celiac disease susceptibility. We carried out a familial study in which 53 Spanish families were genotyped by a polymerase chain reaction (PCR)-based method combined with fluorescent technology. A transmission disequilibrium test was performed to investigate the transmission pattern of the different CCTTTn alleles from parents to affected offspring. The test did not reach any statistically significant difference because none of the CCTTTn repeats was shown to be significantly transmitted to the affected siblings. Our data suggest that the CCTTTn pentanucleotide microsatellite in the NOS2 gene promoter does not play a major role in celiac disease development.
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Affiliation(s)
- Blanca Rueda
- Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain
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40
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Nohara H, Saito Y, Higaki S, Okayama N, Hamanaka Y, Okita K, Hinoda Y. Polymorphisms of the IL-1beta and IL-1beta-inducible genes in ulcerative colitis. J Gastroenterol 2002; 37 Suppl 14:107-10. [PMID: 12572877 DOI: 10.1007/bf03326427] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic disorder of undetermined etiology, but a genetic predisposition to UC is well recognized. Among cytokines induced in UC, interleukin 1 (IL-1) appears to have a central role because of its immunological upregulatory and proinflammatory activities. The aim of this study was to assess whether UC is associated with polymorphisms of the IL-1beta gene and three additional genes inducible with IL-1beta in Japanese subjects. METHODS A total of 96 patients with UC and 106 ethnically matched controls were genotyped at polymorphic sites in IL-1beta, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 3 (MMP-3), and inducible nitric oxide synthase (iNOS) genes, using polymerase chain reaction (PCR)-based methods. RESULTS There was no significant difference in genotype distributions of IL-1beta, MMP-1, MMP-3, and iNOS genes between controls and UC patients in a Japanese population. Also, no significant association of those polymorphisms with various clinical parameters of the patients was found. However, concerning association of age at onset with clinical factors in UC, the frequency of pancolitis was significantly higher in UC patients with age at onset being less than 30 years than in those more than 30 years of age (P = 0.049). CONCLUSIONS No association of the IL-1beta and three IL-1beta-inducible gene polymorphisms with UC was observed in a Japanese population.
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Affiliation(s)
- Hiroaki Nohara
- Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube 755-8505, Japan
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Pascual M, López-Nevot MA, Cáliz R, Koeleman BPC, Balsa A, Pascual-Salcedo D, Martín J. Genetic determinants of rheumatoid arthritis: the inducible nitric oxide synthase (NOS2) gene promoter polymorphism. Genes Immun 2002; 3:299-301. [PMID: 12140750 DOI: 10.1038/sj.gene.6363856] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2001] [Revised: 01/16/2002] [Accepted: 01/16/2002] [Indexed: 11/09/2022]
Abstract
An association study and a linkage analysis were carried out in parallel in order to investigate the association of the inducible nitric oxide synthase (NOS2) gene promoter polymorphism with rheumatoid arthritis (RA) predisposition and/or outcome including a -954G-C mutation, a di-allelic (TAAA)(n) marker and the highly polymorphic (CCTTT). The -954G-C point mutation occurred non-polymorphic and the di-allelic (TAAA)(n) marker was not associated with RA predisposition. The (CCTTT)(n)locus showed a trend for RA association in the case-control study, however, stratification data by Class II status did not yield significant effect and overall, the family study showed no significant association nor linkage for any of the markers under study using TDT and non-parametric linkage respectively. Finally, no influence was detected regarding any of the clinical parameters tested. After evaluating for the first time the influence of NOS2 promoter polymorphism in RA, it seems to have no major effect on disease susceptibility and/or outcome.
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Affiliation(s)
- M Pascual
- Instituto de Parasitologia y Biomedicina López-Neyra, CSIC, Granada, Spain
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42
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Kumaramanickavel G, Sripriya S, Vellanki RN, Upadyay NK, Badrinath SS, Rajendran V, Sukumar B, Ramprasad VL, Sharma T. Inducible nitric oxide synthase gene and diabetic retinopathy in Asian Indian patients. Clin Genet 2002; 61:344-8. [PMID: 12081717 DOI: 10.1046/j.0009-9163.2002.00251.x] [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: 11/20/2022]
Abstract
Nitric oxide, a signal transduction molecule, when modulated causes various diseases including diabetic retinopathy. In diabetes, allelic polymorphism of the inducible nitric oxide synthase (iNOS) gene is associated with retinopathy in the Northern Irish population. In the present study we investigated the Asian Indian population. One hundred and ninety-nine unrelated Asian Indian patients with 15 or more years of type 2 diabetes were divided into two groups: (a) diabetic retinopathy (DR) and (b) diabetic nonretinopathy (DNR) subjects. In these groups the pentanucleotide microsatellite repeat located 2.5 kb upstream of the transcription start site of the iNOS gene was amplified by polymerase chain reaction and analyzed. Eleven alleles, 175-225 bp, were identified. Allele 210 bp was significantly associated with retinopathy (p = 0.044). Individuals carrying this allele had twice the risk of developing retinopathy compared with those who did not carry this allele [odds ratio (OR) - 2.03; 95% CI 0.96-4.35]. Alleles 200 and 220 bp were also significantly associated with no retinopathy and no serious retinopathy complications, respectively. In the Asian Indian population, allele 210 bp of the iNOS gene is a high-risk allele for developing retinopathy and alleles 200 and 220 bp protect an individual from developing retinopathy or its complications.
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Affiliation(s)
- G Kumaramanickavel
- Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
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Konno S, Hizawa N, Yamaguchi E, Jinushi E, Nishimura M. (CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy. J Allergy Clin Immunol 2001; 108:810-4. [PMID: 11692109 DOI: 10.1067/mai.2001.119030] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Several studies have shown that nitric oxide (NO) plays a role in the regulation of the T(H)1/T(H)2 balance, indicating the potential for NO to contribute to the development of atopy and several other allergic diseases, including bronchial asthma. NO synthase 2 (NOS2) is critically involved in the synthesis of NO during several inflammatory states, and the gene encoding NOS2 is located at chromosome 17q11.2-q12, where 2 genome scans have identified a candidate locus for atopy and asthma. OBJECTIVE The 14-repeat allele of the (CCTTT)(n) repeat polymorphism in the NOS2 promoter region is a powerful enhancer of promoter activity in reporter constructs in vitro. We tested whether this potentially functional allele in the NOS2 gene influences the development of atopy and asthma. METHODS We studied a total of 497 unrelated Japanese subjects (141 nonatopic healthy controls, 102 atopic healthy controls, 56 nonatopic asthmatic subjects, and 198 atopic asthmatic subjects). The odds ratio (OR) was calculated for atopy and asthma in carriers of the 14-repeat allele through use of logistic regression models. Atopy was defined as a positive specific IgE level to at least 1 of 10 common inhaled allergens. RESULTS The 14-repeat allele was inversely associated with atopy (OR = 0.42, P < .01). The association remained significant when the model was controlled for asthmatic status (OR = 0.36, P < .01). This allele, however, was associated neither with the development of asthma nor with total serum IgE levels. CONCLUSION Our findings suggest that the (CCTTT)(n) repeat polymorphism in the promoter of the NOS2 gene that affects promoter activity is a risk factor for the development of atopy, and this genetic effect seems independent of asthma.
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Affiliation(s)
- S Konno
- First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan
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Abstract
Nitric oxide (NO) and prostaglandin (PG) E2 produced by NO synthase type 2 (NOS2) and cyclooxygenase type 2 (COX2), respectively, are important mediators in inflammation. There is much information regarding their roles in models of inflammation in mice and in humans with diseases such as rheumatoid arthritis (RA). A variety of stimuli including cytokines, microbial components, immune complexes, and mechanical stress can induce both NOS2 and COX2 mRNA transcription and protein synthesis and enhance inflammation. This has been demonstrated in both mice and humans. NOS2-specific inhibitors reduce inflammation in mice, and COX2-specific inhibitors reduce inflammation in mice and in humans. There is significant cross-talk between PGE2/NO and COX2/NOS2. Treatments that inhibit both NOS2 and COX2 should provide the most potent antiinflammatory effects.
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Affiliation(s)
- J B Weinberg
- Duke University and Medical Center, Durham, NC, USA.
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Modin H, Dai Y, Masterman T, Svejgaard A, Sørensen PS, Oturai A, Ryder LP, Spurkland A, Vartdal F, Laaksonen M, Sandberg-Wollheim M, Myhr KM, Nyland H, Hillert J. No linkage or association of the nitric oxide synthase genes to multiple sclerosis. J Neuroimmunol 2001; 119:95-100. [PMID: 11525805 DOI: 10.1016/s0165-5728(01)00366-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown etiology. Nitric oxide (NO) is a free radical that participates in a variety of biological processes. It is an important mediator in the immune response. Several studies indicate involvement of NO in the pathogenesis of MS. We studied five markers within the three NO synthase genes with regards to susceptibility and disease course in 156 affected sib-pairs and in 96 "benign" and 96 "severe" definite MS patients and 148 controls. We found no significant association or evidence for linkage in our data sets.
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Affiliation(s)
- H Modin
- Department of Neurology, R54, Karolinska Institutet, Huddinge University Hospital, S-121 86, Huddinge, Sweden.
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Xu W, Humphries S, Tomita M, Okuyama T, Matsuki M, Burgner D, Kwiatkowski D, Liu L, Charles IG. Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease. Nitric Oxide 2000; 4:379-83. [PMID: 10944422 DOI: 10.1006/niox.2000.0290] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Allelic frequencies of a (CCTTT)(n) pentanucleotide repeat in the NOS2A promoter region were determined in a total of 1393 unrelated individuals from five specific population groups in four continents: Africa, Europe, Asia, and the Caribbean. There were highly significant differences in allele frequencies between the ethnically diverse populations. The repeat variation may have implications for the selective pressure of malaria or other infectious diseases that may operate at the NOS2 locus.
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Affiliation(s)
- W Xu
- Wolfson Institute for Biomedical Research, University College London, Cruciform Building, London, WC1E 6AU, United Kingdom.
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Warpeha KM, Xu W, Liu L, Charles IG, Patterson CC, Ah-Fat F, Harding S, Hart PM, Chakravarthy U, Hughes AE. Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy. FASEB J 1999; 13:1825-32. [PMID: 10506586 DOI: 10.1096/fasebj.13.13.1825] [Citation(s) in RCA: 99] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Accumulating evidence shows that the severity and rapidity of onset of diabetic retinopathy are influenced by genetic factors. Expression of the nitric oxide synthases is altered in the retinal vasculature in the early stages of diabetic retinopathy. We analyzed the allele distribution of a polymorphic pentanucleotide repeat within the 5' upstream promoter region of the NOS2A gene in samples of diabetic patients. In diabetic patients from Northern Ireland, the 14-repeat allele of the NOS2A marker was significantly associated with the absence of diabetic retinopathy. Carriers of this repeat had 0.21-fold the relative risk of developing diabetic retinopathy than noncarriers of this allele. They also had significantly fewer renal and cardiovascular complications. The ability of differing numbers of (CCTTT)(n) pentanucleotide repeats to induce transcription of the NOS2A gene was analyzed using a luciferase reporter gene assay in transfected colonic carcinoma cells. Interleukin 1beta (IL-1beta) induction was most effective in constructs carrying the 14-repeat allele. When cells were incubated in 25 mM glucose to mimic the diabetic state, IL-1beta induction was inhibited in all cases, but to a significantly lesser extent with the 14-repeat allele. These unique properties of the 14-repeat allele may confer selective advantages in diabetic individuals, which may delay or prevent microvascular complications of diabetes.
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Affiliation(s)
- K M Warpeha
- Department of Medical Genetics, Ophthalmology and Vision Sciences, Queen's University, Belfast, UK
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Abstract
Nitric oxide synthases (NOSs) are ubiquitous in living organisms. However, little is known about the evolution of this large gene family. The first inducible NOS to be described from an invertebrate regulates malaria parasite (Plasmodium spp.) development in the mosquito Anopheles stephensi. This single copy gene shows the highest homology to the vertebrate neuronal isoforms, followed by decreasing homology to endothelial and inducible isoforms. The open reading frame of 1247 amino acids is encoded by 19 exons, which span approximately 33 kilobases. More than 50% of the mosquito exons, distributed around the putative heme, calmodulin, and FAD/NADPH cofactor-binding domains, are conserved with those of the three human genes. Repetitive elements identified within the larger introns include a polymorphic dinucleotide repeat, two tandem repeats, and a putative miniature inverted repeat transposable element. Sequence analysis and primer extension indicate that the upstream promoter is 'TATA-less' with multiple transcription start sites within approximately 250 base pairs of the initiation methionine. Transcription factor binding sites in the 5'-flanking sequence demonstrate a bipartite distribution of lipopolysaccharide- and inflammatory cytokine-responsive elements that is strikingly similar to that described for vertebrate inducible NOS gene promoters.
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Affiliation(s)
- S Luckhart
- Virginia Tech, Department of Biochemistry, 124 Engel Hall, Blacksburg, VA 24061, USA.
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Glenn CL, Wang WY, Morris BJ. Different frequencies of inducible nitric oxide synthase genotypes in older hypertensives. Hypertension 1999; 33:927-32. [PMID: 10205225 DOI: 10.1161/01.hyp.33.4.927] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A locus for essential hypertension has been found recently on chromosome 17 in the general vicinity of the inducible nitric oxide synthase (iNOS) gene (NOS2A at 17cen-q11.2). We therefore tested NOS2A markers for association and linkage with hypertension in affected Australian Anglo-Caucasians. Patients for the association study (n=112) were from our cohort of hypertensives (systolic/diastolic=175+/-25 SD/112+/-19 mm Hg) who were the offspring of 2 hypertensive parents; control subjects (n=164) were normotensives whose parents were both normotensive. The linkage study involved 156 hypertensive sib-pairs. Genotypes for an 8-allele pentameric repeat located 2.6 kb upstream of NOS2A and of a biallelic tetranucleotide repeat 0.7 kb upstream were determined by polymerase chain reaction and automated gene scan analysis. In the association study, the frequency of the minor allele of the biallelic marker was 0.18 in the hypertensives and 0.14 in the normotensives (chi21 df=1.1, P=0.3). Allele frequencies for the multiallelic marker were also similar in each group (chi2 7 df=9.8, P=0.2). Furthermore, no genotypic differences in blood pressure were apparent. In the sib-pair study, SPLINK APM, and MAPMAKERS/SIBS did not indicate excess allele sharing. We also examined genotype as a function of age. In the younger (< 60 years) hypertensives as well as younger or older normotensives, genotype and allele frequency of the biallelic marker was similar (0.12 to 0.14). However, in hypertensives >/=60 years of age, frequency of the minor allele was 0.28 (chi2=7.4, P=0.006). Homozygotes for this allele were rare. Frequency of heterozygotes was 0.19 for normotensives but 0.39 for the older hypertensives (chi2=8.0, P=0.018) and was 0.40 for hypertensive sibs >/=60 years of age with a diastolic pressure >/=100 mm Hg. Furthermore, homozygotes for the major allele were 7 years younger than heterozygotes (P=0.05 by ANOVA). In conclusion, the present study shows (1) no evidence for a role of NOS2A in hypertension and (2) a genotypic difference in frequency of a NOS2A promoter variant in older hypertensives, seen in 2 different cohorts. A possible interpretation of the latter observation is that NOS2A genotype could affect longevity, at least in patients at high risk by having moderate to severe hypertension.
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Affiliation(s)
- C L Glenn
- Hypertension Gene Laboratory, Department of Physiology and Institute for Biomedical Research, The University of Sydney, Australia
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Xu WM, Liu LZ. Nitric oxide: from a mysterious labile factor to the molecule of the Nobel Prize. Recent progress in nitric oxide research. Cell Res 1998; 8:251-8. [PMID: 9934533 DOI: 10.1038/cr.1998.25] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
NO is now known to be an important messenger molecule in biology. It regulates a variety of functions within cells and tissues including vasodilation, neurotransmission and immunological process. This review will focus on the nitric oxide synthase gene family and recent progress on molecular genetic analysis of NOS1, NOS2 and NOS3 genes.
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Affiliation(s)
- W M Xu
- Wolfson Institute for Biomedical Research, Rayne Institute, University College London.
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