Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis

It has proved difficult to identify high-risk patients far atherosclerosis and to determine how they might respond ta medication. Recently, a common p romoter variant of the human stromelysin-T gene has been reported, which ha s been shown to affect the transcription. We investigated whether this poly morphism had any impact on the risk of events, especially restenosis and pr ogression of coronary artery disease and whether the effect was modulated b y treatment with pravastatin. The stromelysin-1 genotype was determined for 496 men with coronary artery disease and cholesterol levels between 4.0 an d 8.0 mmol/L, participating in the Regression Growth Evaluation Satin Study (REGRESS) study, a clinical trial assessing the effect of the lipid-loweri ng drug pravastatin on the progression of atherosclerosis. patients in the placebo group with 5A6A or 6A6A genotypes had more clinical events than pat ients with the 5A5A genotype (26% and 12%, respectively, p = 0.03). In the pravastatin group, the risk of clinical events in patients with 5A6A or 6A6 A genotypes was lower, compared with placebo, whereas it was unchanged in c hose with a 5A5A genotype (p value for interaction: 0.038). Also, the incid ence of repeat angioplasty in the placebo group was greater in patients wit h the 6A6A or 5A6A genotypes, compared with 5A homozygotes (38% and 40%, re spectively, vs 11%, p 0.09). Again, treatment substantially reduced the inc idence in heterozygotes and 6A homozygotes (0% and 15%, respectively), wher eas it was unchanged in 5A homozygotes (28%, p for interaction: 0.002). The se effects were independent of the effects of pravastatin on the lipid leve ls. Thus, this study suggests that the stomelysin-1 promoter polymorphism c onfers a genotype-specific response to medication in determining clinical e vent-free survival and the risk for symptom-driven repeat angioplasty. This variant may therefore oct as a predictor, not only of disease progression, but also of response to therapy and risk of restenosis. (C) 1999 by Excerp ta Medico, Inc.