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1.
Allergol. immunopatol ; 47(2): 159-165, mar.-abr. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-180804

RESUMO

Introduction and Objectives: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. Patients and methods: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. Results: We found a significant difference in the genotype frequencies between the two studied groups (chi2 = 9.855, P = 0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (chi2 = 9.610, P = 0.022). Conclusions: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia


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Assuntos
Humanos , Masculino , Lactente , Pré-Escolar , Criança , Adolescente , Asma/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Mutação/genética , Frequência do Gene , Estudos de Associação Genética , Fenótipo
2.
Artigo em Inglês | MEDLINE | ID: mdl-30268379

RESUMO

INTRODUCTION AND OBJECTIVES: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. PATIENTS AND METHODS: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. RESULTS: We found a significant difference in the genotype frequencies between the two studied groups (χ2=9.855, P=0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (χ2=9.610, P=0.022). CONCLUSIONS: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia.

3.
Eur J Clin Pharmacol ; 74(12): 1567-1574, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30073432

RESUMO

PURPOSE: Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM). METHODS: We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75 mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP. RESULTS: We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p = 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759). CONCLUSIONS: Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals. TRIAL REGISTRATION: Clinical Trials.gov NCT03373552 (Registered 13 December 2017).

4.
Hemoglobin ; 40(6): 411-416, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27829304

RESUMO

The C/EBPE gene, located in 14q11.2, encodes for a B/zip-type transcription factor. The C/EBPɛ is involved in terminal differentiation and functional maturity of granulocyte progenitor cells and in cell apoptosis during myeloid differentiation. A C/EBPE gene has recently been described as a candidate gene involved in clinical variability of ß-thalassemia (ß-thal). In this study, the C/EBPE gene was sequenced in 146 subjects divided into the severe type of ß-thal major (ß-TM) and moderate type of ß-thal intermedia (ß-TI), and a control group. The analysis identified the rs45496295 (C > T) polymorphism in the heterozygous state in 73.9% ß-TI patients, which was not the case in the ß-TM patients or in the control group. Thus, the T allele is consequently associated with the ß-TI group (p = 10-3). According to the Human Splicing Finder (version 3.0, Marseille, France), the presence of the rs45496295 polymorphism leads the creation of a new intronic exotic splicing enhancer (ESE) site. Moreover, the T allele of rs45496295 is associated with a lower transfusion regimen (p = 10-3) and a higher pretransfusion hemoglobin (Hb) rate (p = .006). The comparison of several factors concerning T allele carriers and non-carriers showed that the T allele does not act on the Hb F rate. The T allele of rs45496295, associated with moderate type of ß-thal, seems to modify the C/EBPɛ action, thereby preventing the hemolysis.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Polimorfismo de Nucleotídeo Único , Talassemia beta/genética , Adulto , Hemoglobina Fetal/metabolismo , Hemoglobinas/metabolismo , Hemólise/genética , Humanos
5.
Thromb Res ; 143: 11-6, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27164460

RESUMO

INTRODUCTION: Inherited abnormalities of fibrinogen (FG) are rare coagulation disorders divided into two types: quantitative abnormalities (afibrinogenemia and hypofibrinogenemia) or qualitative abnormalities (dysfibrinogenemia and hypo-dysfibrinogenemia) of circulating fibrinogen. In particular, congenital afibrinogenemia is inherited as an autosomal recessive mode and is usually determined by homozygous or compound heterozygous mutations affecting any of the three fibrinogen genes (FGA, FGB and FGG), resulting in the complete absence or extremely reduced amount of fibrinogen. The aim of the present study was to characterize the fibrinogen abnormalities in two Tunisian families. METHODS: Coagulation studies were performed on the patients and family members. All the exons and the flanking intron regions of fibrinogen genes were screened by direct sequencing. RESULTS: Probands had concomitant bleeding complications with infinitely prolonged standard coagulation assays. Mutational screening of the fibrinogen gene cluster of each proband, disclosed two previously undescribed homozygous point mutations. The first mutation was a major truncation (AαArg252Stop) leads to a severe premature termination codon in the exon 5 of the FGA gene. This mutation defines in vivo the importance of the αC flexible segment in the secretion of a stable fibrinogen molecule. The second afibrinogenemic mutation (BßGly295Ala) occurs in the exon 7 of the FGB gene. This missense mutation would probably lead to significant conformational change not allowing the expression of the fibrinogen protein. CONCLUSION: Current molecular characterization of these two fibrinogen abnormalities confirms the importance of the first portion of αC-region (αC-connector) as well as the Bß globular domain in the secretion processes.


Assuntos
Afibrinogenemia/genética , Fibrinogênio/genética , Mutação de Sentido Incorreto , Adulto , Afibrinogenemia/sangue , Afibrinogenemia/epidemiologia , Idoso , Sequência de Aminoácidos , Sequência de Bases , Coagulação Sanguínea , Criança , Pré-Escolar , Feminino , Fibrinogênio/química , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Conformação Proteica , Tunísia/epidemiologia , Adulto Jovem
7.
Clin Lab ; 62(11): 2139-2143, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28164663

RESUMO

BACKGROUND: In this work, we are interested to study for the first time the extragenic polymorphic marker MP6d9 in cystic fibrosis and healthy cohort in Tunisia to establish the contribution of MP6d9 polymorphism in the phenotypic variability of CF patients. METHODS: Our study enrolled 112 CF patients and 100 healthy controls. The analysis of the polymorphic marker MP6d9 was performed using the PCR-RFLP technique. RESULTS: Statistical difference was found in the genotype and allelic distribution between CF patients and control groups. We found that the 2/2 genotype was higher in CF patients than in controls (58.9% vs 23%). We noted that the 2/2 genotype is associated with severe clinical manifestations. CONCLUSION: Based on the above data, it seems that this genotype has led to the deterioration of our patient's clinical manifestation. This study enabled us to understanding the involvement of the MP6d9 marker in the CF clinical expression in the Tunisian population.


Assuntos
Fibrose Cística/genética , Marcadores Genéticos , Polimorfismo Genético , Adolescente , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Estudos de Casos e Controles , Criança , Pré-Escolar , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Projetos Piloto , Polimorfismo de Fragmento de Restrição , Índice de Gravidade de Doença , Tunísia
10.
Clin Biochem ; 45(15): 1183-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22613267

RESUMO

BACKGROUND AND OBJECTIVES: Analbuminemia is a very rare autosomal recessive disorder. It is an allelic heterogeneous defect caused by a variety of mutations within the albumin gene. We describe in this report two new cases of analbuminemia in Libyans. DESIGN AND METHODS: The 14 coding exons of the human serum albumin (HSA) gene and their intron-exon junctions were PCR amplified. The products were screened for mutations by Denaturing High Performance Liquid Chromatography (DHPLC). Samples with altered DHPLC profiles were sequenced. RESULTS: DNA sequencing revealed the presence of a novol homozygous G➔T transition in the first base of intron 11 (c.1428+1G>T), in both children. This mutation destroys the GT consensus donor sequence found at the 5' end of most intervening sequences and would cause the defective pre-mRNA splicing. CONCLUSION: Molecular diagnosis based on DHPLC and DNA sequencing represents a powerful tool to study molecular defects causing analbuminemia.


Assuntos
Hipoalbuminemia/genética , Albumina Sérica/deficiência , Albumina Sérica/genética , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Líbia , Masculino , Dados de Sequência Molecular , Sítios de Splice de RNA
11.
Mol Biol Rep ; 39(4): 4619-25, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21947948

RESUMO

Hereditary persistence of fetal hemoglobin (HPFH) is a group of genetically heterogeneous conditions characterized by continued expression of fetal hemoglobin (HbF) in adulthood. HPFH may be due not only to point mutations or large deletions in different regions of the cluster ß globin, but also to variations in several polymorphic sequences in this cluster. The objective of this work was to evaluate effects of polymorphic markers within cluster ß globin on HbF expression. For the purpose, we have explored in this first study of Tunisian HPFH four polymorphic regions of ß globin cluster in 68 healthy adults (34 subjects with high levels of HbF and 34 with normal HbF levels). Our results showed that the increase of HbF levels is associated with the -158 Gγ C â†’ T polymorphism, the TG(18)CG(2)CACG, TC TG(9)AG TG(2)CG(2) and TG(11)CG(4) configurations in the second intron of Gγ gene and the -540 ß (AT)(6)T(9) and (AT)(7)T(8) repeated sequences. Among the 34 subjects with raised levels of HbF, approximately 97% carried one or more of these six markers. This study suggests that there is a significant association between certain polymorphic configurations of the ß globin cluster and the increase of HbF levels in healthy individuals.


Assuntos
Hemoglobina Fetal/metabolismo , Família Multigênica/genética , Polimorfismo Genético , Globinas beta/genética , Adolescente , Adulto , Alelos , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Motivos de Nucleotídeos/genética , Fenótipo , Regiões Promotoras Genéticas/genética , Análise de Sequência de DNA , Adulto Jovem
12.
Ann Hum Biol ; 38(5): 561-3, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21329479

RESUMO

BACKGROUND: There are few data on the molecular basis of Cystic Fibrosis (CF) in North Africa, probably due to under-diagnosis. AIM: This is the first study of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in the Libyan population. SUBJECTS AND METHODS: This study analysed the complete coding region and flanking intronic sequences of the CFTR gene in 10 unrelated Libyan CF patients. RESULTS: This study identified four mutations (F508del, c.1670delC, N1303K and E1104X), with a high frequency of the latter. CONCLUSION: Identification of CF mutations facilitates molecular investigation of cystic fibrosis in the Libyan population and helps to provide effective genetic counselling among CF families.


Assuntos
Fibrose Cística/genética , Mutação/genética , Criança , Pré-Escolar , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Líbia , Masculino
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