Mild hyperhomocysteinemia, C677T polymorphism on methylenetetrahydrofolate reductase gene and the risk of macroangiopathy in type 2 diabetes: a prospective study.
ABSTRACT The role of hyperhomocysteinemia as a risk factor for diabetic long-term complications has not been sufficiently evaluated in prospective studies, considering specific correlates of homocysteine (tHcy) concentration and traditional cardiovascular disease (CVD) risk factors. Fasting tHcy, vitamin B12 and folate plasma levels, the common methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, as well as clinical and lifestyle information were assessed in 216 type 2 diabetic patients attending two outpatient clinics, who had a follow-up evaluation at 65 ± 9 months for the incidence of macroangiopathy. At basal evaluation, mild hyperhomocysteinemia (tHcy ≥ 15 μmol/l) was diagnosed in 21.3% of participants. At follow-up, hyperhomocysteinemia and the distribution of MTHFR C677T genotype did not significantly differ according to the incidence of macroangiopathy. Multiple variables adjusted ORs (95% CI) for CVD associated with mild hyperhomocysteinemia were 1.01 (0.37-2.82); P > 0.05; those associated with MTHFR TT genotype were 0.46 (0.15-1.38); P > 0.05. Although the prevalence of hyperhomocysteinemia was higher in diabetic men (26.9%) than in women (16.1%; P > 0.05), similar results were also observed in a separate sex-analysis. At the multivariate analysis, including in the model other potential CVD risk factors, only creatinine clearance was a significant risk factor for the development of macroangiopathy. In this cohort of diabetic subjects, mild hyperhomocysteinemia and the MTHFR TT genotype are not significant risk factors for the development of macroangiopathy; impaired renal function was confirmed as a significant predictor of this complication.
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ABSTRACT: We assessed the contribution of serum homocysteine levels, an independent risk factor for vascular disease, and of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation to the variability of carotid intimal-medial thickness (IMT) in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ninety-five patients (33 males and 62 females, mean age 53 +/- 10 years) without nephropathy or other vascular complications were enrolled. Fasting total serum homocysteine and other biochemical analytes were measured. The MTHFR polymorphism was determined by the polymerase chain reaction. Common carotid IMT and plaques or stenoses in the carotid district were measured by ultrasonography. Serum total homocysteine concentrations were higher in subjects with the mutant (Val/Val) genotype than in those with the Ala/Val plus Ala/Ala genotypes (P = 0.02). On univariate analysis, carotid IMT was significantly associated with age, body mass index (BMI), systolic blood pressure, and total cholesterolemia. No significant association was found between IMT and serum homocysteine or the MTHFR polymorphism, although a slightly greater IMT was observed in the homozygous Val genotypes. On multiple regression analysis, only age and BMI were independently associated with IMT and explained about 40% of IMT variability. The results did not change when the analysis was restricted to the subgroups with or without atherosclerotic plaques in the carotid district. In 95 Italian NIDDM patients without nephropathy, neither basal levels of serum total homocysteine nor the MTHFR C677T polymorphism predicted significant changes in common carotid intimal-medial thickness.Journal of Thrombosis and Thrombolysis 11/1999; 8(3):207-12. · 1.99 Impact Factor
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ABSTRACT: Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.Nature Genetics 06/1995; 10(1):111-3. · 35.21 Impact Factor
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ABSTRACT: High plasma homocysteine level has been associated with increased risk for coronary heart disease (CHD) events in nondiabetic individuals, especially in those with previously diagnosed CHD. In persons with type 2 diabetes mellitus, the association between homocysteine level and cardiovascular disease may be stronger than that in nondiabetic individuals, but no large prospective studies have examined the relationship between homocysteine level and CHD mortality in persons with type 2 diabetes. To investigate whether moderately elevated plasma homocysteine levels are independently related to increased incidence of fatal and nonfatal CHD events in persons with type 2 diabetes. Prospective study. Finnish sample of patients with type 2 diabetes. 462 men and 368 women who were 45 to 64 years of age at baseline. Coronary heart disease mortality and incidence of nonfatal myocardial infarction during the 7-year follow-up. Participants with plasma homocysteine levels of 15 micromol/L or more at baseline had a higher risk for CHD death than those with plasma homocysteine levels less than 15 micromol/L (26.1% and 13.5%, respectively; P = 0.005). The risks for all CHD events were 36.2% and 22.6%, respectively (P = 0.011). In Cox regression analyses, elevated plasma homocysteine level was significantly associated with CHD mortality (P < 0.001) and all CHD events (P = 0.002) even after adjustment for confounding variables, including creatinine clearance. In participants without myocardial infarction at baseline, moderate hyperhomocysteinemia was also associated with CHD mortality and all CHD events in univariate (P < 0.001 and P = 0.006, respectively) and multivariate Cox regression analyses (P < 0.001 and P = 0.004, respectively). In this large cohort of patients with type 2 diabetes, plasma homocysteine level was a strong and independent risk factor for CHD events.Annals of internal medicine 01/2004; 140(2):94-100. · 13.98 Impact Factor