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Genetic Predisposition to Arterial Thrombosis in SLE
Henry I. Bussey, Pharm.D.
Review: Øhlenschlaeger T, Garred P, Madsen HO, Jacobsen S. Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. New England Journal of Medicine 2004; 351:260-267.
The risk of thrombosis - and especially arterial thrombosis - seems to be variable in patients with lupus anticoagulant (LAC) and/or other antiphospholipid antibodies. Although the presence of systemic lupus erythematosis (SLE) may increase the risk of thrombosis in patients with LAC, the presence of SLE often does not appear to explain why some LAC patients have such high risk of recurrent thrombosis. Danish investigators have now identified a genetic factor that appears to contribute to the risk of arterial thrombosis in patients with SLE. Mannose-binding lectin is a liver-derived protein that is involved in the immune system. Variant alleles have been associated with increased risk of infection, the presentation of SLE and rheumatoid arthritis, and early onset and increased severity of atherosclerosis. In the Danish study 7 of 91 patients with SLE were found to be homozygous for the variant alleles and 6 of these 7 had an arterial thromboembolic event during a median follow-up of 9.1 years. By contrast, arterial thromboembolic events occurred in 13 of the 54 (24%) without the variant alleles and 5 of 30 (17%) who were heterozygous for the variant alleles (not significantly different). The difference in arterial thromboembolic events between the 7 homozygous patients and the 84 normal or heterozygous was highly significant (p<0.001) with the majority of the difference being due to differences in acute myocardial infarction (57% vs. 9 and 10%, respectively, p<0.001) although there was a trend toward increased strokes as well (29% vs. 13% and 7%, respectively, p=0.10). Venous thrombosis was not different (14% vs. 17% and 13% for homozygous, normal, and heterozygous, respectively). After adjusting for other risk factors, those with the homozygous alleles were found to have a 7 fold increase in the risk of arterial thromboembolism. The age at diagnosis also was associated with an increased risk (hazard ratio 1.6, p <0.01). Other factors, such as hypertension, smoking, and LAC, were associated with an approximate 2 fold increase in the risk of arterial thromboembolism; but none of these differences were statistically significant, perhaps because of the small number of patients with each condition.
In the future, perhaps such genotyping will allow clinicians to identify those patients at greatest risk for arterial thrombosis and explore which therapies are most effective at preventing these severe complications of SLE.
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