Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis.

Frequently an inherited predisposition to thrombosis remains clinically silent until an additional environmental factor intervenes. The present study aimed to assess distribution of inherited risk factors of venous thrombosis in patients with venous thromboembolism (VTE). The prevalences of factor V Leiden (FV Leiden), prothrombin factor II G20210A (FII G20210A), C677T and A1298C of methylenetetrahydrofolate reductase (MTHFR) mutations were studied in 149 VTE patients and 100 controls. The following key risks were established: previous deep venous thrombosis or pulmonary embolism (23.5%), bed rest (34.2%), immobilisation of lower limb (10.1%), hospitalisation (30.9%) and obesity (28.9%). In 29 (19%) patients and in three (3%) controls FV Leiden was found. A significant association between VTE and FV Leiden was established. There were six (4%) carriers of the FII G20210A among VTE patients and one in the controls. No associations between VTE and MTHFR polymorphisms (C677T, A1298C) were found. In three of 149 patients both FV Leiden and FII G20210A polymorphisms were observed. The mean protein C activity was slightly, though nonsignificantly, smaller in VTE patients. In conclusion, there was a positive association between venous thromboembolism and factor V Leiden. Only a weak trend favouring a relationship between prothrombin factor II G20210A and venous thrombolism was present. No associations between common polymorphisms of methylenetetrahydrofolate reductase and venous thromboembolism were found.     

Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease.

Mild hyperhomocysteinemia is associated with homozygosity for the thermolabile variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) and could increase the risk of venous thromboembolic disease (VTD). Recently, the second A1298C mutation of the MTHFR gene was described. The present study aimed to analyze both mutations of the MTHFR gene and plasma homocysteine levels in subjects with VTD. The study groups comprised 146 patients with VTD and 100 healthy subjects. There were no statistical differences in carrier frequency and allelic frequency for both A1298C and C677T mutations, nor were there any differences encountered between subjects with VTD and controls in either plasma homocysteine levels or according to C677T or A1298C genotypes of MTHFR. In our VTD patients and controls, neither MTHFR 677CT/1298CC nor MTHFR 677TT/1298CC combined genotypes were observed; double heterozygotes (A1298C/C677T) were represented only in 11% of VTD patients, and in 15% of the controls. In conclusion, the polymorphisms C677T and A1298C of MTHFR and fasting plasma homocysteine levels do not seem to be significant risk factors for venous thromboembolic disease.     

Polymorphisms involved in the folate metabolizing pathway and risk of multiple myeloma

Folate and methionine metabolism plays an essential role in both DNA synthesis and methylation. Polymorphisms in the genes of the folate-dependent enzymes have been shown to affect disease susceptibility. We conducted a Korean population-based case-control study to evaluate whether genetic variation in folate metabolism may have a role in the risk of multiple myeloma (MM). The study subjects were 173 patients with MM and 1,700 population-based controls. The polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C > T and 1298 A > C, methionine synthase (MS) 2756 A > G, methionine synthase reductase (MTRR) 66A > G, thymidylate synthase (TS) 28-bp repeat (2R-->3R) and 6-bp deletion/insertion. MS 2756 AG genotypes were associated with a 1.5-fold lower risk of MM (OR = 0.66, 95%CI; 0.43-0.99, P = 0.047). There was no association between MTHFR C677T, A1298C, MTRR A66G, TS 2R-->3R and 6-bp deletion/insertion polymorphisms and MM. These results suggest that MTHFR C677T, A1298C, MTRR A66G, TS 2R-->3R, and 6-bp deletion/insertion do not significantly factor into the pathogenesis of MM in the Korean population, but that MS A2756G polymorphism may play an important role.     

Serum homocysteine,thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE)

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.     

A Case Control Study on the Contribution of Factor V-Leiden,Prothrombin G20210A,and MTHFR C677T Mutations to the Genetic Susceptibility of Deep Venous Thrombosis

Background: Insofar as the inherited prothrombotic single nucleotide polymorphisms (SNPs) factor V G1691A (FV-Leiden), prothrombin (PRT) G20210A, and methylenetetrahydrofolate reductase (MTHFR), C677T are inherited risk factors of venous thromboembolism (VTE), the aim of this study was to determine the prevalence of single and combined SNPs in 198 patients with documented deep venous thrombosis (DVT), and 697 control subjects, and to estimate the associated risks.Methods: Factor V-Leiden, PRT G20210A, and MTHFR C677T were analyzed by PCR and restriction fragment length polymorphism (RFLP).Results: The prevalence of the heterozygote and homozygous variants for FV-Leiden (52.02 vs. 14.78%, RR 6.28), PRT G20210A (19.2 vs. 3.6%; RR 6.38), and to a lesser extent the T/T genotype of MTHFR C677T (20.71 vs. 11.0%; RR 1.49) were higher among DVT patients vs. controls, respectively. Two or more SNPs were detected in 90 of 198 patients (45.5%) and in 60 of 697 controls (8.6%), with odds ratios of 16.754 for joint occurrence of FV-Leiden and PRT G20210A, 10.471 for FV-Leiden and MTHFR C677T, and 6.283 for PRT G20210A SNPs and MTHFR 677T/T. Logistic regression analysis showed a further increased odds for FV-Leiden in combination with PRT G20210A (85.198) or homozygous MTHFR C677T (81.133), and to a lesser extent for PRT G20210A in combination with homozygous MTHFR C677T (20.812).Conclusions: This indicates that FV-Leiden and PRT G20210A, more than MTHFR C677T, are important risk factors for DVT, and that the presence of more than one prothrombotic SNPs was associated with a significant risk of DVT.     

Methylenetetrahydrofolate reductase C677T genotype and venous thromboembolic disease

BACKGROUND: Many studies have suggested an increased risk of venous thromboembolism (VTE) in patients with mild hyperhomocysteinemia. The C677T mutation in the MTHFR gene has recently been described as a cause of mild hyperhomocysteinemia. OBJECTIVES: To investigate the potential of the C677T mutation in the MTHFR gene in its homozygous state as a risk factor for VTE. METHODS: Case-control study design. The presence of the mutation was determined in all consecutive patients referred from July 1994 to September 1997 and in whom the diagnosis was duly confirmed. Analysis was carried out in a subgroup of VTE patients free from both acquired and genetic risk factors (factor-V mutation and/or prothrombin gene mutation). A control group consisted of 105 volunteer blood donors. RESULTS: In the 366 patients with a confirmed VTE, 253 presented acquired risk factors and 58 were carriers of the factor-V Leiden mutation and/or G20210A mutation of the prothrombin gene. In the remaining 55 patients, VTE was considered as 'unexplained', and the frequency of the C677T mutation MTHFR was 21.8% in its homozygous state and 34.5% in its heterozygous state. In the control group, 9.5% were found homozygous and 34.3% heterozygous. The odds ratio for having VTE in the presence of the mutation in its homozygous state was 2.9 (95% CI 1. 0-8.6). CONCLUSION: This study suggests that the homozygous C677T mutation in the MTHFR gene might be a risk factor of VTE in patients with spontaneous events and without other common genetic risk factors.     

Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases

Elevated plasma homocysteine is increasingly being recognized as a risk factor for coronary artery disease (CAD). Although there is general agreement on the importance of micronutrients and genetic predisposition to elevated plasma homocysteine, the exact influence of the known prevalent mutations in genes which regulate homocysteine metabolism is not clear. We studied 376 cases of individuals with premature CAD with respect to their fasting and post-methionine load (PML) total homocysteine (tHcy) concentrations. We also determined the presence or absence of the T833C and G919A mutations of the cystathionine-beta-synthase (CBS) gene, the C677T mutation of the methylene tetrahydrofolate reductase (MTHFR) gene, and the A2756G transition of the B12 dependent methionine synthase (MS) gene. Our objectives were therefore both to confirm the relationship of plasma homocysteine with premature CAD and to examine the importance of genetic influence on both fasting and PML homocysteine. Approximately 32% of the CAD patients had fasting hyperhomocysteinemia and 16% had PML hyperhomocysteinemia. Of these, 8.5% had both forms of hyperhomocysteinemia (combined hyperhomocysteinemia). The T133C mutation in the CBS gene and the thermolabile C677T mutation in the MTHFR gene seem to play an important role in the subset of individuals with combined hyperhomocysteinemia. The A2756G transition in the MS gene is not associated with elevated plasma tHcy. Many cases (47%) of hyperhomocysteinemia are not associated with micronutrient deficiencies, impaired renal function, and/or currently known genetic mutations. Further work is needed to study whether unknown mutations, particularly those residing in the intronic sequences of the genes involved in homocysteine metabolism, other environmental factors, or interaction of gene, nutrient, and environmental factors may be the cause of currently unexplained cases of mild hyperhomocysteinemia.     

MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of diabetic nephropathy in type 2 diabetes patients

Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were implicated in the pathogenesis of diabetic nephropathy (DN) in many ethnic groups. This study addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients, 267 patients with normoalbuminuria, and 400 control subjects. C677T and A1298C genotypes were determined by PCR-RFLP analysis, and homocysteine levels were measured by ELISA. A1298C and C677T were highly prevalent among T2DM patients, with allele frequencies of 0.26 and 0.36, respectively. Higher mutant 677T allele and 677C/T and 677T/T genotypes of C677T SNP, but not A1298C SNP, together with 677C/1298A, 677C/1298C, and 677T/1298A haplotypes were seen in DN patients compared to normoalbuminuric patients, (p<0.001). Plasma homocysteine was positively associated with MTHFR 677T/T genotype among the three groups, and was significantly elevated in double heterozygous DN patients but not in normoalbuminuric patients or controls. Logistic regression analysis with DN as dependent variable showed that homocysteine (OR, 1.153) and MTHFR 677T/T (OR, 9.799) were the only variables associated with DN, after adjusting for possible confounding variables. C677T, but not A1298C, SNP, is a risk factor for DN, presumably acting by elevating homocysteine levels.     

Lack of association between the C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene and venous thromboembolism in Northwestern Greece.

BACKGROUND: Hyperhomocysteinemia has been associated with venous thrombosis. Under known and unknown conditions the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is accompanied by elevated levels of homocysteine. However, the relationship of this mutation with venous thromboembolism (VTE) remains controversial. The purpose of this study was to evaluate the association of the MTHFR mutation with VTE. METHODS: The presence of the C677T mutation in the MTHFR gene was investigated in a population of 176 consecutive patients with a history of venous thromboembolism and in a control group of 300 healthy subjects, using DNA analysis. RESULTS: The prevalence of homozygosity in the patient group was 13.6% and in healthy subjects 10%. The odds ratio for venous thromboembolism in the presence of the homozygous genotype (677TT) was 1.4 (95% confidence interval (C.I.), 0.8 to 2.5), which was not statistically significant. CONCLUSIONS: Homozygosity for the T677 allele of the MTHFR gene, although slightly more prevalent in patients compared to controls, has not been found in association with venous thromboembolism.     

Analysis of thrombophilic genetic mutations in patients with Sheehan`s syndrome: is thrombophilia responsible for the pathogenesis of Sheehan`s syndrome?

The gene mutations of Factor V R506Q (FV-Leiden), prothrombin (FII G20210A), methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C and PAI-1 4G/5G are well-established risk factors for thrombosis. We aimed to investigate the prevalence of these gene mutations and their possible impact on the development of pathogenesis in patients with Sheehan’s syndrome (SS). 40 female patients with SS compared to a control group of 45 healthy women. The presence of FV-Leiden, FII G20210A, MTHFR C677T, MTHFR A1298C and PAI-1 4G/5G gene mutations were assessed by polymerase chain reaction analysis with a light cycler analyzer. An odds ratio of greater than one is considered to increase the risk of SS disease as found in Factor V Leiden, FII G20210A, MTHFR C677T, MTHFR A1298C and PAI-1 4G/5G polymorphism, as follows respectively: 1.13, 1.85, 6.00, 8.14 and 1.45. MTHFR C677T and MTHFR A1298C polymorphism were found significantly higher in SS patients than the control group (P < 0.001), however FV-Leiden, FII G20210A and PAI-1 4G/5G polymorphism showed no significant difference (P > 0.05). The level of plasma total homocysteine (tHcy) was significantly higher in patients with SS than in the control group (P < 0.001). We suggest that the genetic mutations of FV-Leiden, FII G20210A, MTHFR C677T, MTHFR A1298C and PAI-1 4G/5G increase the risk of SS. Also, high plasma tHcy levels may be a risk factor for the development of SS.     

Effect of the MTHFRC677T variant on risk of venous thromboembolism: interaction with factor V Leiden and prothrombin (F2G20210A) mutations

Odds ratios for the MTHFR C677T variant were determined in a large case–control study of 558 unselected patients with venous thromboembolism and 500 control subjects. The odds ratios for MTHFR C677T heterozygosity and homozygosity were 1.07 (95%CI 0.84–1.36) and 0.71 (95%CI 0.48–1.03). In patients with the factor V Leiden or the F2 G20210A mutations there was no apparent increase in risk of venous thromboembolism due to the MTHFR C677T polymorphism.
Thrombophilia testing should not include genotyping for the MTHFR C677T polymorphism.     

血浆同型半胱氨酸及其代谢酶基因多态性与溃疡性结肠炎的相关性研究

目的 探讨血浆同型半胱氨酸(Hcy)、叶酸和维生素B12水平及Hcy代谢酶基因多态性与溃疡性结肠炎(UC)的关系.方法 收集310例UC患者和936名正常对照者,采用聚合酶链反应-限制性片断长度多态性(PCR-RELP)法检测亚甲基四氢叶酸还原酶(MTHFR)C677T、A1298C、甲硫氨酸合成酶(MTR) A2756G和甲硫氨酸合成还原酶(MTRR) A66G基因多态性;并从中随机选取88例UC患者和100名正常对照者,采用循环酶法检测血浆Hcy水平,微粒子免疫化学发光法检测叶酸和维生素B12浓度.结果 UC患者MTHFR A1298C、MTR A2756G和MTRRA66G突变的等位基因及基因型频率均明显增高(P值均<0.01).UC患者Hcy平均水平为(21.73±6.59)mmol/L,较正常对照组显著增高[(12.47±5.01)mmol/L,P<0.01],而叶酸和维生素B12平均水平分别为(11.25±6.19)nmol/L和(322.81±128.47)pmol/L,明显较正常对照组降低[(15.28±7.72)nmol/L和(422.59±129.36)pmol/L,P值均<0.01].Logistic回归分析提示血浆Hcy、叶酸和维生素B12浓度是UC的独立危险因素(P值均<0.01).结论 Hcy代谢酶基因多态性及血浆Hcy、叶酸和维生素B12水平异常与UC明显相关,为临床采用叶酸、维生素B12补充疗法治疗UC提供了理论依据.     

Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults

A modestly elevated total plasma homocysteine concentration (tHcy) is generally accepted as an independent and graded risk factor for various pathologies, including vascular diseases, neural tube defects, Alzheimer disease, and pregnancy complications. We analyzed 5 common functional polymorphisms in enzymes involved in homocysteine metabolism (ie, methylenetetrahydrofolate reductase [MTHFR] 677C>T and 1298A>C, methionine synthase [MTR] 2756A>G, cystathionine beta-synthase [CBS] 844ins68, and methionine synthase reductase [MTRR] 66A>G) in 452 young adults, and quantified their independent and interactive effects on tHcy concentrations. Serum folate, red cell folate, vitamin B(12), and tHcy concentrations were significantly influenced by MTHFR 677C>T genotypes. A particularly strong interaction was observed between the MTHFR 677TT genotype and serum folate, which led to a high tHcy phenotype that was more pronounced in males. The genetic contribution to the variance in tHcy was estimated to be approximately 9%, compared with approximately 35% that could be attributed to low folate and vitamin B(12). Our study indicates that dietary factors are centrally important in the control of tHcy levels in young adults with additional, but somewhat weaker, genetic effects. These data underscore the potential benefits that may be gained by improving the dietary status of young adults, and provide support for the implementation of folate/B-vitamin food fortification programs.     

Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B12 levels and the extent of coronary artery disease

The question of whether mild hyperhomocysteinemia is a risk factor for coronary artery disease (CAD) has long been debated and is still unclear. We investigated whether there is a link between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms or plasma homocysteine and CAD. This is a case-control study that included 2,121 consecutive patients (cases) with angiographically proved CAD and 617 patients without CAD (controls). MTHFR gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B(12) concentrations were determined and coronary angiography was performed in all subjects. The distribution of MTHFR gene C677T genotypes in patients (or controls) was: CC-genotype in 915 cases, 43.1% (266 controls, 43.1%); CT-genotype in 955 cases, 45.0%, (283 controls, 45.9%); and TT-genotype in 251 cases, 11.9% (68 controls, 11.0%) (p = 0.84). The distribution of MTHFR gene A1298C genotypes in patients (or controls) was: AA-genotype in 973 cases, 45.9% (281 controls, 45.5%); AC-genotype in 905 cases, 42.7% (284 controls, 46.0%); and CC-genotype in 243 cases, 11.4% (52 controls, 8.5%) (p = 0.07). Patients with CAD had higher levels of plasma homocysteine (12.9 +/- 5.1 vs 11.9 +/- 4.5 micromol/L, p <0.001) and lower levels of folate (9.5 +/- 3.1 vs 9.9 +/- 3.8 ng/ml, p = 0.008) than controls. After adjustment for other risk factors for CAD, plasma homocysteine (p = 0.89), MTHFR gene C677T (p = 0.38), or A1298C polymorphisms (p = 0.13) were not independent correlates of CAD. This study demonstrated that MTHFR gene C677T or A1298C polymorphisms are not associated with the presence of angiographic CAD. Although there is an apparent association between elevated levels of homocysteine and CAD, this association is not independent of conventional cardiovascular risk factors.     

Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment

The inherited thrombophilias--deficiencies of protein C, protein S, and antithrombin III--and the prothrombotic polymorphisms factor V G1691A and factor II G20210A predispose patients toward venous thromboembolism (VTE). The aim of this study was to determine the prevalence of single and combined prothrombotic factors in patients with idiopathic VTE and to estimate the associated risks. The study group consisted of 162 patients referred for work-up of thrombophilia after documented VTE. The controls were 336 consecutively admitted patients. In all subjects factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were analyzed by specific polymerase chain reactions and restriction enzymes. Activities of antithrombin III and protein C, free protein S antigen, and lupus anticoagulant were determined in a subset of 109 patients who were not receiving oral anticoagulants. The prevalences of heterozygotes and homozygotes for factor V G1691A and factor II G20210A among patients and controls were 40.1% versus 3.9% and 18.5% versus 5.4%, respectively (P=0.0001). The prevalence of homozygotes for MTHFR C677T in patients was 22.8% and in controls, 14.3% (P=0.025). Heterozygous and homozygous factor V G1691A, factor II G20210A, and homozygous MTHFR C677T were found to be independent risk factors for VTE, with odds ratios of 16.3, 3.6, and 2.1, respectively. Two or more polymorphisms were detected in 27 of 162 patients (16.7%) and in 3 of 336 controls (0.9%). Logistic regression analysis disclosed odds ratios of 58.6 (confidence interval [CI], 22.1 to 155.2) for joint occurrence of factor V and factor II polymorphisms, of 35.0 (CI, 14.5 to 84.7) for factor V and MTHFR polymorphisms, and of 7.7 (CI, 3.0 to 19.6) for factor II and MTHFR polymorphisms. Among 109 patients in whom a complete thrombophilic work-up was performed, 74% had at least 1 underlying defect. These data indicate that in most patients referred for evaluation of thrombophilia due to idiopathic VTE, 1 or more underlying genetic predispositions were discernible. The presence of >1 of the prothrombotic polymorphisms was associated with a substantial risk of VTE.     

C677T substitution in the methylenetetrahydrofolate reductase gene as a risk factor for venous thrombosis and arterial disease in selected patients.

BACKGROUND AND OBJECTIVE: Hyperhomocysteinemia, due to a combination of genetic and environmental factors, is considered to be a risk factor for vascular disease. Individuals with the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR), due to homozygous C677T MTHFR gene mutation, have significantly raised plasma levels of homocysteine and may be at increased risk of vascular disease. However, it is still controversial a direct association between C677T homozygosity and the occurrence of vascular disease is still controversial. DESIGN AND METHODS: To clarify the contribution of C677T MTHFR mutation in arterial occlusive disease (AOD) or venous thromboembolism (VTE), we performed a case-controlled study including 160 cases with AOD and 180 cases with VTE attending our referral center and compared them with 200 matched healthy controls. MTHFR gene mutation was evaluated by PCR and odds ratios (OR) and the 95% confidence intervals (CI) were used to estimate the risk for venous or arterial thrombosis. RESULTS: There was a high prevalence of homozygotes for the mutated MTHFR allele among the whole group of cases with arterial disease (OR = 2.35, p = 0.001). Considering the AOD cases with and those without associated risk factors for arterial disease separately the difference remained significant only in the latter group (p = 0.168 and P<0.001 respectively). In contrast, the prevalence of mutated homozygotes among the whole group of cases with VTE was not significantly different from that in the control group (OR = 1.67; p = 0.070). Excluding VTE cases with inherited thrombophilia or with circumstantial risk situations the value increased in both subgroups (OR = 2.26; p = 0.006 and OR = 2.03; p = 0.033 respectively). Considering only VTE cases with neither inherited thrombophilia nor circumstantial risk situations the risk increased further (OR = 2.57; p = 0.017). INTERPRETATION AND CONCLUSIONS: These data suggest that in selected patients homozygosity for the MTHFR mutation increases the risk of both arterial and venous thromboses and that differences in selection criteria for the patient group may be responsible in part for the controversial association of the MTHFR mutation and vascular disease.     

A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease

We assessed the effect of a recently described mutation in the MTHFR gene (1298 A --> C) on the risk of deep venous thrombosis (DVT) by determining its prevalence in 190 patients with verified DVT and in age-, race- and gender-matched controls. MTHFR 1298 A --> C was found in 42.1% of patients and in 41.1% of controls. The OR for venous thrombosis was 1.07 (95% CI 0.70-1.65) for heterozygotes and 0.83 (95% CI 0.33-2.08) for homozygotes. The OR for the factor V Leiden (FVL) mutation was 3.40 (95% CI 1.22-9.48), for FII 20210 G --> A was 5.22 (95% CI 1.12-24.2) and for MTHFR 677 C --> T, 1.24 (95% CI 0.82-1.87). No significant increased risk for venous thrombosis was found when MTHFR 1298 A --> C was coinherited with FVL (OR 2.85, 95% CI 0.88-9.23), FII 20210 G --> A (OR 7.19, 95% CI 0.87-59.4) or MTHFR 677 C --> T (OR 1.44, 95% CI 0.71-2.92). These data do not support a critical role of MTHFR 1298 A --> C in the predisposition to DVT.     

Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma

Lymphoproliferative diseases are characterized by chromosomal aberrations, and susceptibility may depend on inherited activity of enzymes required for DNA synthesis and methylation. We analysed genetic polymorphisms for methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in Caucasians with non-Hodgkin's lymphoma (NHL; n = 151), multiple myeloma (MM; n = 90) and 299 control subjects. The MS 2756 AG/GG genotypes were significantly under-represented in NHL (26.2%) vs control subjects (37.2%; P = 0.02), and conferred a 2.4-fold lower risk of follicular (odds ratio = 0.41, 95% confidence interval: 0.19-0.88, p = 0.02) but not diffuse large B-cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects.     

Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease

Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover, data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and gender-matched healthy subjects. Significantly higher frequency of 677T allele and homozygous 677T/T genotype were seen in patients vs. control subjects; the distribution of A1298C alleles and genotypes being comparable in the two groups. Specific MTHFR haplotypes comprising 677C/1298A (P < 0.001) and 677T/1298A (P < 0.001) were negatively and positively associated with CAD, respectively. Plasma homocysteine concentration was significantly higher in 677T/T genotype with respect to 677C/C and 677C/T genotypes in patients and controls, but homocysteine levels were generally comparable between both groups. Univariate analysis identified 677T/1298A (P = 0.033) haplotype to be positively associated with CAD, which remained significant by multivariate analysis after adjusting for a number of covariates (P = 0.038). MTHFR C677T, but not A1298C SNPs, is associated with CAD and with elevated homocysteine levels in a Tunisian population. The negative and positive association of the 1298A allele with CAD being indicative of a neutral (absent) effect of the A1298C SNP on disease pathogenesis.     

Factor V G1691A,Prothrombin G20210A,and Methylenetetrahydrofolate Reductase [MTHFR] C677T Gene Polymorphism in Angiographically Documented Coronary Artery Disease

BACKGROUND: Single point mutations in the genes coding for factor V [G1691A; Leiden], prothrombin [PRT; G20210A], and methylenetetrahydrofolate reductase [MTHFR, C677T] were shown to be major inherited predisposing factors for venous thromboembolism. However, their contribution in the development of coronary artery disease [CAD] remains controversial. The aim of the study was to examine the association of these mutations in CAD. METHODS: A total of 96 patients with angiographically-demonstrated CAD [mean age 55.3 +/- 11.3], and 404 healthy subjects [mean age 50.7 +/- 8.9] were recruited into the study. Fasting plasma homocysteine was determined by HPLC, and genotype analysis was assessed by PCR-RFLP. RESULTS: The carrier frequency of factor V-Leiden (14.6% vs. 15.1%, p = 0.617) and PRT G20210A (3.1% vs. 3.0%; p = 0.936) were similar between patients and controls, respectively. In contrast, the frequency of the MTHFR variant C677T was 71.9% among patients compared with 45.5% in controls (p < 0.001), of which the T/T genotype was significantly higher among patients (31.3%) than controls (4.5%; p < 0.001). Significantly higher homocysteine levels were seen among T/T genotype in both groups compared to non-T/T carriers (p < 0.05), and among patients compared with controls (18.47 +/- 3.73 micromol/L vs. 16.28 +/- 4.16 micromol/L). In addition, the coexistence of MTHFR C677T with FV-Leiden was seen in 10.4% of CAD patients compared 6.9% of controls (p = 0.001). CONCLUSION: While results from this study clearly demonstrate a strong association of hyperhomocysteinemia and homozygosity of the MTHFR C677T, but not FV-Leiden or PRT G20210A, mutations with confirmed CAD, they also suggest a potential role for factor V-Leiden in MTHFR C677T carriers.