基质金属蛋白酶 3（MMP3）多态性对与降压治疗相关的卒中风险的遗传药理学效应：与高血压相关治疗的遗传学研究。
Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: the genetics of hypertension associated treatment study.
机构信息
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 32594, USA.
出版信息
Stroke. 2011 Feb;42(2):330-5. doi: 10.1161/STROKEAHA.110.593798. Epub 2010 Dec 23.
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.
背景与目的
包括中风在内的动脉粥样硬化性血栓疾病具有共同的病因，即动脉粥样硬化，而动脉粥样硬化的易感性具有遗传成分。基质金属蛋白酶-3（基质金属蛋白酶-3[MMP3]）调节动脉基质组成，是动脉粥样硬化血栓形成的候选基因。MMP3 的常见多态性改变表达水平，并影响动脉粥样硬化的进展和斑块稳定性。作为高血压相关治疗遗传学研究的一部分，该研究是抗高血压和降脂治疗预防心脏病试验的辅助研究，我们评估了 MMP3 中的 5A/6A 多态性，以确定其与中风的关联，并确定其是否改变降压药物治疗的临床结局反应。
方法
采用多变量调整 Cox 回归模型，包括基因型与降压药物类别的交互作用检验，来研究 MMP3 5A/6A 多态性对中风发生率的影响。
结果
与接受氯噻酮治疗且基因型为 6A/6A 的参与者相比，随机接受赖诺普利治疗且基因型为 6A/6A 的个体中风发生率更高（风险比=1.32；95%CI，1.08 至 1.61；P=0.007），接受赖诺普利治疗的 5A/6A 个体中风发生率更低（交互作用风险比=0.74；95%CI，0.53 至 1.04；P(交互作用)=0.08），而接受赖诺普利治疗的 5A/5A 个体中风发生率最低（交互作用风险比=0.51；95%CI，0.31 至 0.85；P(交互作用)=0.009）。在接受氨氯地平或多沙唑嗪与氯噻酮治疗的患者中，基因型对中风发生率无药物遗传学差异。
结论
与接受氯噻酮治疗的患者相比，MMP3 6A/6A 基因型与高血压患者接受赖诺普利治疗时中风风险增加相关，而接受赖诺普利治疗的 5A/5A 个体则存在保护作用。如果这一发现得到证实，MMP3 5A/6A 基因型的基因筛查可能成为选择最佳降压治疗的有用工具。临床试验注册- URL：http://www.clinicaltrials.gov。独特标识符：NCT00563901。
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