☆ 4.7 Article

Pharmacogenetic Effect of the Stromelysin (MMP3) Polymorphism on Stroke Risk in Relation to Antihypertensive Treatment The Genetics of Hypertension Associated Treatment Study

STROKE (2011)

Journal

STROKE

Volume 42, Issue 2, Pages 330-335

Publisher

LIPPINCOTT WILLIAMS & WILKINS

DOI: 10.1161/STROKEAHA.110.593798

Keywords

stroke; pharmacogenetics; matrix metalloproteinase-3; antihypertensive agents

Funding

National Heart, Lung, and Blood Institute, Bethesda, MD [HL63082, N01-HC-35130]

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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.

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Predictive values of baseline matrix metalloproteinase 9 levels in peripheral blood on 3-month outcomes of high-risk patients with minor stroke or transient ischemic attack

Min Zhang, Xia Meng, Yuesong Pan, Yilong Wang, Xingquan Zhao, Liping Liu, Jiejie Li, Hongyi Yan, Xiangrong Liu, Hui Zhang, Lijuan Pang, Yongjun Wang

Summary: This study aimed to explore the relationship between baseline levels of matrix metalloproteinase 9 (MMP9) in peripheral blood and the outcomes in patients with acute minor stroke and transient ischemic attack (TIA). The results showed that higher baseline MMP9 levels were associated with an increased risk of poor functional outcomes, which might be related to stroke recurrence and combined vascular events.

EUROPEAN JOURNAL OF NEUROLOGY (2022)