Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects

Several studies have indicated that mild to moderate hyperhomocystinemia is a common cause of arterial occlusive disease. Whether hyperhomocystinemia per se is an independent risk factor for vein thromboembolism (VTE) is stil l somewhat controversial, Both genetic and nutritional factors influence pl asma homocysteine levels. Therefore, we evaluated plasma total homocysteine (tHcy), folate, and vitamin B-12 levels and established, by polymerase cha in reaction, the presence of the C677T mutation (A223V) in the methylenetet rahydrofolate reductase (MTHFR) gene in 220 cases with VTE without well-est ablished prothrombotic defects. As a control group, 220 healthy subjects fr om the same geographic area as the cases were investigated. Hyperhomocystin emia was defined as a plasma tHcy level above the 95th percentile in the co ntrols (18.05 mu mol/L). Hyperhomocystinemia was found in 16% of cases (odd s ratio=3.59; P<0.001); deficiencies of folate (<2.47 ng/mL) or vitamin B-1 2 (<165 pg/mL), defined as values below the 5th percentile in controls, wer e found in 17.7% (P<0.001) and 12.3% (P=0.015) of cases, respectively. The homozygous condition for the MTHFR mutation (VV) was present in 28.2% of ca ses and 17.7% of controls (odds ratio=1.82; P=0.013). Comparing only the id iopathic forms of VTE (n=80/220; 36.3%) with normal controls, individuals w ith hyperhomocystinemia, or individuals homozygous for MTHFR mutation incre ased the odds ratios to 4.03 (P=0.005) and 2.11 (P=0.018), respectively. No statistically significant difference was observed in the MTHFR genotype di stribution of cases and controls with hyperhomocystinemia (P=0.386); howeve r, the normal MTHFR genotype (AA) appeared in control subjects only when tH cy levels were below the 80th percentile (10.57 mu mol/L) of the distributi on, whereas in case patients, it was present at the highest tHcy levels. A strong association between mutated homozygosity (VV), low folate levels, an d hyperhomocystinemia was found in both groups. We conclude that in patient s with VTE who do not have coexisting prothrombotic defects, hyperhomocysti nemia increases the risk of developing idiopathic and venous thrombosis; th e homozygous condition for the MTHFR mutation confers a moderate risk but, together with low folate levels, it is the main determinant of mild hyperho mocystinemia in normal and thromboembolic populations.