Mild homocysteinemia occurs surprisingly often in patients with premature vascular disease. We studied the possible enzymatic sources of this mild hyperhomocysteinemia and the control of homocysteine levels in plasma by treatment of patients with the cofactors and cosubstrates of homocysteine catabolism. We assessed homocysteine metabolism in 131 patients who had premature disease in their coronary, peripheral, or cerebrovascular circulation by using a standard oral methionine-load test Impaired homocysteine metabolism occurred in 28 patients. We assayed levels of the primary enzymes of homocysteine catabolism in cultured skin fibroblast extracts from 15 of these 28 patients. The patients' cystathionine 0-synthase levels (3.68±2.52 nmol/h per milligram of cell protein, mean±SD) were markedly depressed compared with those from 31 healthy adult control subjects (7.61 ±4.49, P<.001). The patients' levels of 5 -methyltetrahydrofolate: homocysteine methyltransferase were normal. While betalne: homocysteine methyltransferase was not expressed in skin fibroblasts, 24-hour urinary betaine and fyiV-dimethylglycine measurements were consistent with normal or enhanced remethylation of homocysteine by betaine: homocysteine methyltransferase in the 13 patients tested. When treated daily with choline and betaine, pyridoxine, or folic acid, there was a normalization of the postmethionine plasma homocysteine level in 16 of 19 patients. Our results indicate that mild homocysteinemia in premature vascular disease may be caused by either a folate deficiency or deficiencies in cystathionine /3-synthase activity. It does not necessarily involve deficiencies of either 5-methyltetrahydrofolate: homocysteine methyltransferase or betaine: homocysteine methyltransferase. Effective treatment regimens are also defined. (Arteriosder Thromb. 1993;13:1253-1260 KEYWORDS • coronary heart disease • 5-methyltetrahydrofolate: homocysteine methyltransferase • cystathionine 0-synthase • betaine: homocysteine methyltransferase

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We explored the associations between G-->A mutations of factor V and factor VII genes and the Hae III polymorphism of the fibrinogen gene and the severity of coronary artery disease (CAD), as assessed angiographically in 545 white Australian patients (388 male and 157 female) aged < or = 65 years. We also assessed the relations with other potentially atherogenic variables. Elevated fibrinogen levels were associated with more severe CAD (P < .05), but none of the factor V, factor VII, and fibrinogen DNA variants were predictive of CAD severity, as assessed by the number of significantly diseased vessels (> 50% luminal obstruction). The rare allele frequencies of factor V (A allele), factor VII (M2 allele), and fibrinogen (H2 allele) were .025, .114, and .201 for men and .022, .077, and .169 for women, respectively, and were not different from those in healthy whites. In the patient population, there was a strong, positive association between lifetime smoking dose (in pack-years) and circulating fibrinogen levels (r = .184, P = .001). This association was stronger than that between current smoking habit and fibrinogen and is consistent with a dosage effect. However, there was no significant contribution of fibrinogen genotype to fibrinogen levels in this patient population. We conclude that elevated fibrinogen levels are associated not only with the occurrence of CAD but also with more severe CAD and that measurement of DNA variants of the factor V, factor VII, and fibrinogen genes that we assessed may not provide information in predicting CAD severity in addition to that obtained by measuring circulating levels of the relevant clotting factors. There is, moreover, a positive dosage effect (in pack-years) of smoking on circulating fibrinogen levels.