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 gen etic and environmental factors, is considered to be a risk factor for vascu lar disease. Individuals with the thermolabile variant of methylenetetrahyd rofolate reductase (MTHFR), due to homozygous C677T MTHFR gene mutation, ha ve significantly raised plasma levels of homocysteine and may be at increas ed risk of vascular disease. However, a direct association between C677T ho mozygosity 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 perfor med a case-controlled study including 160 cases with AOD and 180 cases with VTE attending our referral center and compared them with 200 matched healt hy 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 ve nous or arterial thrombosis. Results. There was a high prevalence of homozygotes for the mutated MTHFR a llele among the whole group of cases with arterial disease (OR=2.35, p=0.00 1). Considering the AOD cases with and those without associated risk factor s for arterial disease separately the difference remained significant only in the latter group (p=0.168 and p<0.001 respectively). In contrast, the pr evalence 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=0.0 70). Excluding VTE cases with inherited thrombophilia or with circumstantia l risk situations the value increased in both subgroups (OR=2.26; p=0.006 a nd OR=2.03; p=0.033 respectively). Considering only VTE cases with neither inherited thrombophilia nor circumstantial risk situations the risk increas ed further (OR=2.57; p=0.017). Interpretation and Conclusions. These data suggest that in selected patient s homozygosity for the MTH-FR mutation increases the risk of both arterial and venous thromboses and that differences in selection criteria for the pa tient group may be responsible in part for the controversial association of the MTHFR mutation and vascular disease. (C) 1999, Ferrata Storti Foundati on.