Though there is considerable evidence, both epide-miological and experimental, that homocysteine is a causative factor in vascular disease, there are data that contradict this conclusion. First, though cross-sectional and case-control studies fairly consistently demonstrate that hyperhomocysteinemia is associated with vascular disease, some prospective studies have found no relationship between baseline homocysteine levels and risk of incident vascular events. Second, several studies have found no relationship between the MTHFR 667C!T polymorphism and venous thrombosis, despite the association of this polymorphism with elevated plasma homo-cysteine levels.
With these observations in mind, a plausible alternative hypothesis has been put forward to explain the association between hyperhomocysteinemia and vascular disease. One of the organs that can be significantly affected by vascular disease is the kidney. Reduced kidney function caused by atherosclerosis may lead to renal insufficiency and reduced capacity to metabolize homocysteine. In this way, hyperhomocysteinemia may actually result from vascular disease. This hypothesis remains to be tested. The possibility of a vicious cycle, i.e., one in which vascular disease causes homocysteine to become elevated in the blood, which in turn induces further vascular damage, must also be considered.
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