Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study.
OBJECTIVE: To examine the relationship between plasma homocysteine, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism, and the risk of arterial and/or venous thrombosis in systemic lupus erythematosus (SLE). METHODS: Plasma homocysteine and MTHFR polymorphism were determined in a retrospective cohort of 175 patients with SLE. Associations between homocysteine levels and antiphospholipid antibodies, renal function, and drug therapy were analyzed. RESULTS: Patients with arterial thrombosis had higher homocysteine concentration than nonthrombotic patients (20.6+/-10.2 vs 13.2+/-6.8 micromol/l; p < 0.001). The crude odds ratio for arterial thrombosis for the highest versus lowest quartile of homocysteine was 4.4 (95% CI 1.3-14.9). After adjustment for other risk factors the odds ratio remained significant (3.7; 95% CI 1.2-13.0). Increased plasma homocysteine was not associated with venous thrombosis. A significant correlation was found between homocysteine and creatinine (r=0.57, p < 0.0001) or the use of methotrexate. Homocysteine levels were higher in patients using corticosteroids and lower in patients using oral contraceptive drugs. This finding may be biased by impaired renal function in patients using corticosteroids and the advice to stop estrogen-containing contraceptives in female patients upon an episode of thrombosis. The distribution of MTHFR genotypes was 50% for homozygous wild type, 42% for heterozygous, and 8% for homozygous mutant, with a similar distribution among patients with or without a history of thrombosis. CONCLUSION: Raised levels of homocysteine are associated with arterial thrombosis in patients with SLE. Mutation in the MTHFR gene does not explain the raised levels, and renal failure is by far the most frequent cause.