Association of HLA-DR/DQ polymorphism with Alzheimer's disease.

BACKGROUND: Alzheimer's 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.

Apolipoprotein E genotypes associated with Alzheimer disease and concomitant stroke.

BACKGROUND: The ɛ4 allele of the apolipoprotein E (APOE) gene is a well-characterized genetic risk factor for Alzheimer disease (AD). The association between stroke and a higher risk for AD has also been reported. Our study sought to determine the relationship between the APOE gene and AD and the comorbid risk of stroke. METHODS: The subjects of this study consisted of 48 patients with AD and 48 members of a control group. All subjects were genotyped for APOE. RESULTS: The results clearly show a significant increased risk of AD in carriers of the APOE ε3/ε4 genotype (P = .003, odds ratio [OR] = 4.1) or ε4 allele (P = .001, OR = 4.2). The risk for stroke in AD patients was also increased for carriers of the APOE ε3/ε4 genotype (P = .02, OR = 9.0) and for carriers of the APOE ε4 allele (P = .004, OR = 5.5). CONCLUSIONS: The present study is the first to establish a relationship between APOE ε4 and concomitant AD and stroke in the Tunisian population.

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

BACKGROUND: Genetic risk factors play an important role in the pathogenesis of Alzheimer's 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. OBJECTIVE: To verify the association between MTHFR C677T and A1298C polymorphisms and Alzheimer's disease. METHOD: This 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. RESULT: Genetic 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. CONCLUSION: The MTHFR A1298C polymorphism is a possible risk factor for Alzheimer's disease.

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 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.

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.

Maternal cerebral venous thrombosis, uncommon but serious disorder, pathologic predictors and contribution of prothrombotic abnormalities.

Cerebral venous thrombosis (CVT) is a rare complication during pregnancy or the puerperium. Our aim was to identify thrombotic risk profiles that predispose to maternal CVT.The study comprised 151 individuals. All participants had a thrombotic workup that included the following: genetic markers: factor V Leiden G1691A and G20210A prothrombin mutations, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms; protein assays: protein C, protein S and antithrombin; other tests: blood typing and screening for hyperhomocysteinemia. Maternal CVT has been associated with factor V Leiden, the prothrombin G20210A mutation, protein C deficiency and hyperhomocysteinemia. We also speculate that non-O blood groups and preeclampsia could be independent risk factors for CVT.

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

BACKGROUND AND OBJECTIVE: Myasthenia 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. PATIENTS AND METHODS: HLA 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. RESULTS: Myasthenia 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). CONCLUSION: Our 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.

Effects of prothrombotic markers and non-O blood group in maternal venous thromboembolism during pregnancy and postpartum.

Our aim was to assess thrombophilic risk factors and the non-O blood group as contributors to the development of venous thromboembolism during pregnancy and the postpartum period. A total of 199 women underwent blood typing and an extensive thombophilia screening. Factor V Leiden, FII G20210A, protein C deficiency and non-O blood group were significantly associated with venous thromboembolism during pregnancy and postpartum period. A known thrombophilic factor may have consequences for future pregnancies and could have implications for clinical practice. For this reason, women with a history of thromboembolism should be screened for thrombophilia. The non-O blood group could also have an important influence, especially when concomitant with another prothrombotic risk factor mainly pregnancy and thrombophilia.

Thrombophilic disorders: a real threat to patients with end-stage renal disease on hemodialysis and at the time of renal transplantation.

Management of end-stage renal disease is the mainstay of prevention of renal vascular complications and kidney rejection. We sought to describe the association of some disorders such as diabetic nephropathy, polycystic renal disease, hypertension, and thrombophilia with renal failure and discuss possible mechanisms explaining the implication of the thrombophilic states in kidney allograft thrombosis and renal rejection. Five hundred and sixty-eight patients were included in this case-control study and multivariate analysis was applied. Cases and controls were tested for all major types of thrombophilia. Diabetic nephropathy, autosomal dominant polycystic kidney disease, hypertension, and smoking are the strongest causal agents of end-stage renal disease in Tunisia. It should also be noted that the prevalence of factor V Leiden (P = 0.05) and protein C deficiency (P = 0.005) were significantly higher in ESRD patients awaiting renal transplantation than controls. The present study has raised the possibility that thrombophilic factors may play a pathophysiological role in renal failure. These results will serve as a basis for anticoagulant prophylaxis aimed at preventing kidney rejection and renal allograft thrombosis.

Association of MTHFR A1298C polymorphism (but not of MTHFR C677T) with elevated homocysteine levels and placental vasculopathies.

Our aim in this study was to investigate the association between elevated homocysteine levels and the two MTHFR polymorphisms, C677T and A1298C, with several pregnancy complications such as recurrent pregnancy loss, preeclampsia, placental abruption and intrauterine growth retardation. In 203 women with different placental vasculopathies, we determined the MTHFR C677T and the A1298C prevalence and their relative association to elevated homocysteine levels. The mean plasma homocysteine level was significantly higher in the pathologic groups when compared with the control group. We identified the carriage of the MTHFR A1298C polymorphism as a significant risk factor for vascular-related pregnancy complications. Women with MTHFR A1298C polymorphism or elevated homocysteine levels have an increased risk of placental vasculopathies. The MTHFR A1298C mutation also had a positive impact on elevated homocysteine levels. The lack of association between the MTHFR C677T polymorphism and pregnancy morbidities needs further studies.

Role of thrombophilia in vascular access thrombosis among chronic hemodialysis patients in Tunisia.

Vascular access thrombosis represents a serious and common problem in hemodialysis patients. 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 some thrombophilias and vascular access thrombosis in hemodialysis patients. Seventy-eight patients undergoing dialysis (between May 2007 and September 2009) were selected as subjects. This sample was divided into two groups; a case group of 28 patients who had sustained one or more thrombotic events that resulted in vascular access failure and a control group of 50 patients, who had never had a thrombotic occlusion of a functioning permanent dialysis access. Antithrombin, protein C and protein S levels were measured. Also, both groups were tested for the factor V Leiden mutation, the prothrombin G20210A mutation, the methylene tetrahydrofolate reductase C677T and A1298C mutations. Among genetic mutations of factor V Leiden, prothrombin G20210A and methylene tetrahydrofolate reductase genes, the C677T methylene tetrahydrofolate reductase mutation was the only significant genetic cause of vascular access thrombosis (P=0.005). Our data demonstrated a significantly increased risk of vascular access thrombosis in carriers of the C677T methylene tetrahydrofolate reductase mutation.

The status of thrombophilic defects and non-O blood group as risk factors for gestational vascular complications among Tunisian women.

AIMS: Our objectives were to assess inherited thrombophilia and non-O blood group for the risk of gestational vascular complications among the Tunisian population. METHODS: This study comprised 203 test subjects with adverse pregnancy outcomes including recurrent pregnancy loss, intra-uterine growth retardation, pre-eclampsia and placental abruption. Each subgroup was matched with 100 controls and analyzed separately. All patients were evaluated for factor V Leiden, factor II G20210A mutations and for non-O blood group. Protein S, protein C and antithrombin levels were determined and deficiencies noted. RESULTS: The factor V Leiden mutation, non-O blood group and protein C deficiency had the highest incidences among patients both as a whole and in the 4 subgroups. The factor II G20210A mutation, protein S and antithrombin deficiencies were not statistically significant risk factors. CONCLUSION: Our results provide evidence for a significant association between the factor V mutation and placental abruption. Furthermore, we found that this and the non-O blood group independently increased the risk for intra-uterine growth retardation in our population.