Nasreddine Gritli

Methylenetetrahydrofolate reductase (C677T and A1298C) polymorphisms, hyperhomocysteinemia, and ischemic stroke in Tunisian patients.

OBJECTIVEnThe present study evaluated the role of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C gene polymorphisms and correlated these results with plasma homocysteine (Hcy) levels in Tunisian ischemic stroke (IS) patients.nnnMETHODSnOverall, 84 patients with IS were included and compared with 100 healthy controls. The most common stroke risk factors were investigated. Fasting plasma Hcy levels were measured. Genotyping of the MTHFR C677T and A1298 polymorphisms was studied by polymerase chain reaction.nnnRESULTSnAside from tobacco and alcohol use, the other studied factors were significant risk factors for IS. Mean plasma Hcy levels were significantly higher in IS patients than in controls (16.1 ± 8.28 μmol/L versus 8.76 ± 3.48 μmol/L, P < 10(-3)). Significant associations were found with both the MTHFR 677(CT + TT) and 1298 (AC + CC) genotypes in comparison with controls (P < 10(-3)). A significant synergistic interaction was also found with the double heterozygote MTHFR 677CT/1298AC (P < 10(-3)). Homocysteine levels were significantly higher in IS patients with the MTHFR C677T variant (CT and TT genotypes) (P < 10(-3)); however, the difference was not significant with the MTHFR A1298C variant (AC and CC genotypes) (P = .31).nnnCONCLUSIONnThe MTHFR C677T and A1298 polymorphisms (individually or in concert) and hyperhomocysteinemia represent important risk factors for IS. Elevated Hcy levels were found to be associated with the MTHFR C677T variant; however, no significant association was found with the MTHFR A1298C variant.

Association of methylenetetrahydrofolate reductase polymorphisms with susceptibility to Alzheimer's disease

BACKGROUNDnGenetic risk factors play an important role in the pathogenesis of Alzheimers disease (AD). In this case-control study, we examined the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and their correlation with this pathology.nnnOBJECTIVEnTo verify the association between MTHFR C677T and A1298C polymorphisms and Alzheimers disease.nnnMETHODnThis work was conducted as a case-control study. Cases consisted of thirty-eight patients and 100 individuals without dementia constituted the control group. Genotyping of MTHFR polymorphisms was performed on patients and controls.nnnRESULTnGenetic analyses did not indicate a significant association between the MTHFR C677T mutation and AD (C/T: 63.15% versus 39%, p=0.087). However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3)). Our data suggest an association between the MTHFR A1298C mutation and AD; however, the MTHFR C677T mutation did not contribute to susceptibility for AD.nnnCONCLUSIONnThe MTHFR A1298C polymorphism is a possible risk factor for Alzheimers disease.

Association of HLA-DR-DQ polymorphisms with diabetes in Tunisian patients

OBJECTIVEnType 1 diabetes (T1D) is a polygenic disease whose principal locus is the human leukocytes antigen (HLA) region. The aim of this study was to evaluate HLA DR-DQ alleles and to asses them as risk factors for type 1 diabetes in the Tunisian population.nnnMATERIALS AND METHODSnA total of 119 subjects with diabetes were tested for HLA class II alleles and compared with 292 healthy controls. HLA DRB1 and DQB1 alleles were genotyped using polymerase chain reaction sequence-specific primers (PCR-SSPs).nnnRESULTSnThe results revealed that the most susceptible haplotypes are the DRB1(*)03-DQB1(*)02 (pc<10(-3)) and DRB1(*)0401-DQB1(*)0302 (pc=0.001). (pc denotes Bonferroni corrected probability values.) The most protective haplotypes are DRB1(*)11-DQB1(*)03, DRB1(*)07-DQB1(*)02, and DRB1(*)13-DQB1(*)06 (pc=0.0026, pc=0.0065, and pc=0.02 respectively). Our results showed some particularities unique to Tunisians, there was a lack of a significant protective effect of the DRB1(*)15-DQB1(*)06 haplotype that usually is the dominant combination associated with protection in most other populations.nnnCONCLUSIONnTunisian diabetic patients share the most susceptible and protective HLA haplotypes with Caucasians and those in neighbor Mediterranean countries. This is most likely explained by the history and admixture events of Tunisia and North Africa.

Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients.

BACKGROUND AND OBJECTIVEnMyasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. MG has been shown to be associated with many human leukocyte antigens (HLA) in different populations. The aim of this study was to investigate the probable association between HLA-DR/DQ alleles and MG in Tunisian patients.nnnPATIENTS AND METHODSnHLA DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) with 48 MG patients and 100 healthy individuals serving as the control group.nnnRESULTSnMyasthenia gravis in Tunisian patients was found to be associated with the following alleles (p(c) denotes Bonferroni corrected probability values): HLA-DRB1*03 (p(c)<10(-3)), DRB1*04 (p(c)=0.005), DQB1*02 (p(c)=0.002) and, DQB1*03 (p(c)=0.007).nnnCONCLUSIONnOur data demonstrated a new HLA-MG predisposition with DRB1*04. The DRB1*03, DRB1*04, DQB1*02, and DQB1*03 alleles also could be predisposing genetic factors for MG in the Tunisian population.

Association of methylenetetrahydrofolate reductase A1298C polymorphism but not of C677T with multiple sclerosis in Tunisian patients

BACKGROUND AND OBJECTIVEnMultiple sclerosis (MS) is a chronic neurological disease characterized by central nervous system (CNS) inflammation and demyelination of nerve axons. The aim of this study was to investigate a possible association between the methylenetetrahydrofolate reductase (MTHFR) gene and multiple sclerosis in Tunisian patients.nnnPATIENTS AND METHODSnThe genotyping of two missense variants of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C was performed in 80 multiple sclerosis patients and 200 healthy controls.nnnRESULTSnNo significant differences were found in the frequency of the MTHFR C677T polymorphism between MS patients and healthy controls. However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3); C/C: 13.75% versus 0%, p<10(-3), respectively).nnnCONCLUSIONnAlthough our preliminary findings suggest no association between the MTHFR C677T variants and MS, there is evidence to suggest a significant association between the MTHFR A1298C polymorphisms and MS.

HLA class II alleles and multiple sclerosis in Tunisian patients

OBJECTIVEnThe aim of our study was to investigate the association of HLA-DRB1 and -DQB1 alleles with multiple sclerosis (MS) in a Tunisian population and their effect on age at onset and disease severity.nnnMETHODSn58 MS patients and 105 healthy controls were genotyped for HLA class II alleles by PCR-SSP technique.nnnRESULTSnAn association of MS with HLA-DRB1*15 was found (14.7% vs 3.8%, OR (95% CI)=4.34 (1.69-11.39), p(c)=2.5×10(-3)) after Bonferronis correction. Moreover, the DRB1*15-DQB1*06 (13.8% vs 2.8%, OR (95% CI)=5.44 (1.92-17.41), p(c)=1.1×10(-3)) and DRB1*04-DQB1*04 (8.6% vs 1.9%, OR (95% CI)=4.86 (1.36-21.62), p(c)=0.028) haplotypes were found to confer a susceptibility to multiple sclerosis.nnnCONCLUSIONnTo our knowledge, this is the first study performed to analyze the association of HLA-DRB1/DQB1 alleles on MS susceptibility in Tunisia. The modern Tunisian gene pool shows some degree of heterogeneity and reflects a significant gene flow from Mediterranean regions.

Association of HLA-DR/DQ Polymorphism With Alzheimer’s Disease

Background:Alzheimers disease (AD) is a complex disorder, resulting from an interaction between environmental and genetic factors. Several studies have addressed the association of AD with major histocompatibility complex (MHC) polymorphisms without arriving at any definite conclusions. The human leukocyte antigen (HLA) region is the key susceptibility locus in many immunological diseases. The aim of this study was to investigate the probable association between HLA-DR/DQ alleles and AD in Tunisian patients. Methods:HLA-DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers with 55 AD patients and 100 healthy individuals serving as the control group. Results:AD in Tunisian patients was found to be associated with the following alleles (Pc denotes Bonferroni corrected probability values): HLA-DRB1*15 (Pc < 10–3), DRB1*04 (Pc = 0.03) and DQB1*06 (Pc < 10–3). Two haplotypes found to be associated with the disease were DRB1*1501/DQB1*0602 (Pc < 10–3) and DRB1*0402/DQB1*0302 (Pc = 0.02). Conclusions:The authors believe this to be the first research linking the haplotypes DRB1*1501/DQB1*0602 and DRB1*04/DQB1*0302 with AD. Larger studies in other populations will be important to support the present findings of the possible susceptible risk of HLA-DR/DQ in AD.

Thrombophilic polymorphisms – factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T – in Tunisian patients with cerebral venous thrombosis

Cerebral venous thrombosis (CVT) has been associated with thrombophilic defects. We performed a study to evaluate the role of three single nucleotide polymorphisms (SNP), factor V Leiden G1691A (FVL), prothrombin gene mutation G20210A (FII-G20210A) and methylenotetrahydrofolate reductase variant C677T (MTHFR-C677T), as risk factors for CVT in Tunisian patients. A single center case-control study (26 patients with CVT and 197 controls) was performed. Genomic DNA was tested for the three SNP. The principle finding was the association between FVL and CVT (p<0.001, Odds ratio=6.1, 95% confidence interval=2.3-16.5). However, neither the FII-G20210 (p=0.536) nor the homozygous MTHFR-C677T genotype (p=0.325) variant contributed to the risk of CVT in these Tunisian patients.

Lack of association between factor V Leiden and prothrombin G20210A polymorphisms in Tunisian subjects with a history of myocardial infarction

BACKGROUNDnMyocardial infarction is a multifactorial disease. It is provoked by occlusions in the coronary arteries resulting from exposure to multiple risk factors.nnnOBJECTIVEnTo study the risk of myocardial infarction associated with the gene polymorphisms of factor V Leiden and factor II (G20210A).nnnMATERIALS AND METHODSnCases consisted of 100 myocardial infarction patients who were hospitalized in the Principal Military Hospital of Tunis and 200 control subjects with no history of myocardial infarction.nnnRESULTSnThe prevalence of the factor V Leiden was higher in myocardial infarction patients (9%) than in control subjects (6%) with an OR=1.55 (95% CI=0.58-4.12), whereas the prevalence of prothrombin G20210A mutation was 3% and 2.5% in the patient and control groups, respectively [OR=1.21 (95% CI=0.22-5.94)].nnnCONCLUSIONnOur results indicate that neither factor V Leiden nor the prothrombin G20210A contributed to the risk factors for myocardial infarction.

Lack of association between monocyte protein-1 (MCP-1) –2518 A > G chemoattractant and C–C chemokine receptor 2 (CCR2) Val64Ile polymorphisms and multiple sclerosis in a Tunisian population

Chemokines and their receptors are known to mediate inflammation and tissue damage in autoimmune disorders such as multiple sclerosis (MS). Multiple sclerosis is an inflammatory disease of the central nervous system, characterized by myelin damage and neurological complications. Monocyte chemoattractant protein-1 (MCP-1) interacts with the C-C chemokine receptor 2 (CCR2) and plays a role in the migration of leukocytes into the central nervous system, thus contributing to the T cell-mediated pathogenesis of MS. Genomic DNA obtained from 58 MS patients and 72 healthy controls was tested for the MCP-1 -2518 A>G and CCR2 Val64Ile polymorphisms using polymerase chain reaction-restriction fragment length polymorphism analysis. Neither the MCP-1 -2518G (p=0.43) nor the CCR2 64Ile (p=0.52) variant contributed to the risk of MS in Tunisians.