Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: the genetics of hypertension associated treatment study

Abstract

Background and purpose: Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the Genetics of Hypertension Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine whether it modifies clinical outcome response to blood pressure-lowering drugs.

Methods: The effect of the MMP3 5A/6A polymorphism on stroke rates was examined by using multivariate-adjusted Cox regression models, including a test for interactions between genotype and antihypertensive drug class.

Results: Compared with participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard ratio=1.32; 95% CI, 1.08 to 1.61; P=0.007) and 5A/6A individuals taking lisinopril had lower stroke rates (hazard ratio(interaction)=0.74; 95% CI, 0.53 to 1.04; P(interaction)=0.08), whereas 5A/5A individuals taking lisinopril had the lowest stroke rate (hazard ratio(interaction)=0.51; 95% CI, 0.31 to 0.85; P(interaction)=0.009). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin vs chlorthalidone.

Conclusions: The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared with patients treated with chlorthalidone, whereas a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00563901.

Conflict of interest statement

Conflicts of Interest/Disclosures: Authors report having no conflicts of interest to disclose.

Figures

Figure 1

Results based on the treatment by genotype interaction term from a Cox regression model adjusted for age, total cholesterol, African American race, sex, current smoking, SBP, DBP, and diabetes status. The MMP3 polymorphism was modeled as a three-level (genotypic) factor. All hazard ratios and P-values are in reference to individuals with the 6A/6A genotype who were randomized to chlorthalidone.