Meriem Mrad

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

OBJECTIVE The 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. METHODS Overall, 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. RESULTS Aside 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). CONCLUSION The 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 HLA-DR-DQ polymorphisms with diabetes in Tunisian patients

OBJECTIVE Type 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. MATERIALS AND METHODS A 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). RESULTS The 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. CONCLUSION Tunisian 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 methylenetetrahydrofolate reductase (A1298C and C677T) polymorphisms with retinal vein occlusion in Tunisian patients

The role of two polymorphisms C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) gene in the etiology of retinal vein occlusion (RVO) has not been adequately clarified. The aim of this study was to examine the prevalence of these polymorphisms among RVO Tunisian patients with and without systemic risk factors. Seventy-two patients with retinal vein occlusion (RVO) were studied. The control group included140 people matched for age, sex, and risk factors. Participants in the study were genotyped for the MTHFR C677T and A1298C polymorphisms. The genotyping was performed by PCR-RFLP. No significant differences were found in the frequencies of the three genotypes (AA, AC, CC) of the MTHFR A1298C polymorphism between RVO patients and healthy controls. However, the prevalence of the group of mutated genotypes (AC+CC) of the missense variant MTHFR A1298C was significantly different between patients and controls (16.67% vs. 6.42%, p=.01). Additionally, the frequency of the CT genotype as well as the group of combined mutated genotypes (CT+TT) for the C677T variant was significantly higher among RVO patients compared with controls (p<10(-3), p<10(-3)). This suggests an association between this polymorphism and RVO. Large study populations would be required to understand more completely the contribution of these markers in the risk of RVO.

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

BACKGROUND AND OBJECTIVE Multiple 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. PATIENTS AND METHODS The 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. RESULTS No 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). CONCLUSION Although 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.

Association of HLA-DR/DQ polymorphism with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in Tunisian patients.

BACKGROUND AND OBJECTIVE Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder of the peripheral nervous system (PNS). The aim of this study was to investigate associations between HLA-DR/DQ alleles and CIDP in Tunisian patients. PATIENTS AND METHODS HLA DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) with 36 CIDP patients and 100 healthy individuals serving as the control group. RESULTS CIDP in Tunisian patients was found to be associated with the HLA-DRB1*13 allele (pc=0.03) (where pc denotes the Bonferroni corrected probability value). Moreover, the two haplotypes, DRB1*13/DQB1*06 (22.22% of patients vs. 8.5% of controls, pc=0.017) and DRB1*07/DQB1*03 (13.88% of patients vs. 3% of controls, pc=0.005), were found to confer a susceptibility to CIDP. CONCLUSION To our knowledge, this is the first study performed to analyze the association of HLA-DRB1/DQB1 alleles on CIDP susceptibility in a Tunisian population.

Role of methylenetetrahydrofolate reductase A1298C polymorphism in cerebral venous thrombosis.

The association between the methylenetetrahydrofolate reductase (MTHFR) gene and cerebral venous thrombosis (CVT) remains controversial. This study principally investigated the potential role of the MTHFR A1298C variant and CVT. The genotyping of the A1298C variant of the MTHFR gene was performed in 35 CVT patients and 200 healthy controls. The frequency of A1298C genotype among CVT patients was significantly higher compared with controls (P < 10−3), suggesting an association between this polymorphism and CVT. To our knowledge, there are no previous reports assessing the correlation between the MTHFR A1298C variant and CVT. Large study populations would be required to understand the contribution of this marker in the risk of CVT.

Methylenetetrahydrofolate Reductase (MTHFR) (C677T and A1298C) Polymorphisms and Vascular Complications in Patients with Type 2 Diabetes

OBJECTIVES To assess whether 2 polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, are risk factors for vascular complications in Tunisian patients with type 2 diabetes mellitus. METHODS The MTHFR polymorphisms were genotyped, and plasma homocysteine levels were evaluated in 160 Tunisian patients with type 2 diabetes mellitus. RESULTS Prevalence of the 2 heterozygous polymorphisms of the thermolabile MTHFR gene (CT and AC) was encountered more commonly in patients with diabetes mellitus than in the healthy controls (p<10-3). Subjects with diabetes had significantly higher homocysteine (Hcy) levels than the control subjects; however, there was no statistical difference in plasma Hcy values between carriers of mutant genotypes (CT/TT for C677T and AC/CC for A1298C) and wild types (CC and AA) in patients with diabetes. Retinopathy was found to be a vascular complication in patients with either the 677CT or the 1298(AC+CC) genotype more commonly than in those with the wild-type genotypes (p=0.003; OR=3.2, 95% CI, 1.4 to 7.4; p<10-3; OR=5.9, 95% CI, 2.7 to 13). Only patients who carry the A1298C mutation (AC+CC) are at risk for at least 1 complication (p=0.002). Double heterozygous mutants were at the greatest risk for retinopathy and for suffering at least 1 complication (p<10-3). CONCLUSIONS Studies involving a larger study population and various ethnic groups are required before ruling out the role of MTHFR gene in type 2 diabetes mellitus and in vascular complications.

Association Between Thrombophilic Gene Mutations and the Risk of Vascular Access Thrombosis in Hemodialysis Patients.

The cause of thrombosis in hemodialysis vascular access is considered to be of a multifactorial nature, including stenosis of the venous or arterial connection. Therefore, identification of relevant thrombotic risk factors could lead to an improved antithrombotic therapy. This case control study was performed to evaluate the relationship between Factor V (G1691A and A4070G) and Factor II polymorphisms and vascular access thrombosis in hemodialysis patients. One hundred and twenty‐one patients undergoing dialysis were selected as subjects. This sample was divided into two groups; a case group of 60 patients who had sustained one or more thrombotic events that resulted in vascular access failure and a control group of 61 patients, who never had a thrombotic occlusion of a functioning permanent dialysis access. Our data demonstrated a significantly increased risk of vascular access thrombosis in carriers of the mutant FV (G1691A and A4070G) polymorphisms (P < 0.05).Further studies on a large‐scale population and other genetic variants will be needed to find candidate genes for vascular access thrombosis in hemodialysis patients.

Association of HLA-DR/DQ polymorphisms with schizophrenia in Tunisian patients.

BACKGROUND AND OBJECTIVES The hypothesis that human leukocyte antigens (HLAs) confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in family samples. Our goal was to evaluate the role of HLA in the risk of developing schizophrenia in a Tunisian population. DESIGN AND SETTINGS Blood samples for this case-control study were collected from patients of the Department of Psychiatry at the Military Hospital of Tunisia between July 2012 and May 2013. METHODS A total of 140 patients with schizophrenia were recruited for genetic analysis. Controls included 100 persons matched for age, sex, and risk factors. Participants were tested for HLA class II alleles. HLA-DRB1 and HLA-DQB1 alleles were genotyped using polymerase chain reaction sequence-specific primers. RESULTS This study indicates that the alleles most responsible for disease susceptibility are DRB1*03 (P<10−3) and DQB1*02 (P<10−3) (P denotes probability values). The most protective alleles are DRB1*13 (P=.013) and DQB1*05 (P<10−3). Further results revealed that DRB1*0301/DQB1*0201(P<10−3), DRB1*0401/DQB1*0301 (P<10−3) and DRB1*1101/DQB1*0301 (P<10−3) are haplotypes most conducive to disease susceptibility. CONCLUSION The present findings support an association between schizophrenia and the HLA-DR-DQ locus among a Tunisian population. To our knowledge, this is the first study performed to analyze the association of HLA DRB1/DQB1 alleles on schizophrenia susceptibility in Tunisia.

Association of FV G1691A Polymorphism but not A4070G With Coronary Artery Disease

Coronary artery disease (CAD) is one of the chief causes of death in the world. Several hypotheses have been promoted as for the origin of the disease, among which are genetic predispositions and/or environmental factors. The aim of this study was to determine the effect of factor V (FV) gene polymorphisms (Leiden, G1691A [FVL] and HR2 A4070G) and to analyze their association with traditional risk factors in assessing the risk of CAD. Our study population included 200 Tunisian patients with symptomatic CAD and a control group of 300 participants matched for age and sex. All participants were genotyped for the FVL and HR2 polymorphisms. Multivariate logistic regression was applied to analyze independent factors associated with the risk of CAD. Our analysis showed that the FVL A allele frequency (P < 10–3, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.6-4.9) and GA genotype (P < 10–3, OR = 4.03, 95% CI = 2.1-7.6) are significantly more prevalent among patients with CAD compared to those controls and may be predisposing to CAD. We further found that the FVL mutation is an independent risk factor whose effect is not modified by other factors (smoking, diabetes, hypertension, dyslipidemia, and a family history of CAD) in increasing the risk of the disease. However, analysis of FV HR2 variation does not show any statistically significant association with CAD. The FVL polymorphism may be an independent risk factor for CAD. However, further investigations on these polymorphisms and their possible synergisms with traditional risk factors for CAD could help to ascertain better predictability for CAD susceptibility.