Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2011;6(8):e23609. doi: 10.1371/journal.pone.0023609. Epub 2011 Aug 24.
MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.
Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested.
There were 38,698 participants genotyped for at least one of the polymorphisms included here. For MMP9 R668Q (rs2274756), lower hazard ratios (HRs) were found for AA subjects for most outcomes when treated with chlorthalidone versus amlodipine (eg., CCHD: GG = 1.00, GA = 1.01, AA = 0.64; P = 0.038). For MMP9 R279Q (rs17576), modest pharmacogenetic findings were observed for combined CHD and the composite CVD outcome. For MMP12 N122S (rs652438), lower HRs were observed for CHD in subjects carrying at least one G allele and being treated with chlorthalidone versus lisinopril (CHD: AA = 1.07, AG = 0.80, GG = 0.49; P = 0.005). In the lisinopril-amlodipine comparison, higher HRs were observed for participants having at least one G allele at the MMP12 N122S locus (CHD: AA = 0.94, AG = 1.19, GG = 1.93; P = 0.041). For MMP12 -82A>G (rs2276109), no pharmacogenetic effect was found for the primary outcome, although lower HRs were observed for AA homozygotes in the chlorthalidone-amlodipine comparison for HF (P = 0.015).
We observed interactions between antihypertensive drugs and MMP9 and MMP12 for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions.
基质金属蛋白酶-9（MMP-9）和 -12 参与组织重塑，可能在心血管疾病（CVD）中发挥作用。我们评估了 4 种 MMP 多态性和 3 种降压药物与心血管结局的相关性。
来自一项双盲、随机、临床试验的高血压患者（n = 42418）被随机分配至氯噻酮、氨氯地平、赖诺普利或多沙唑嗪治疗（平均随访时间为 4.9 年）。主要结局为冠心病（CHD）。次要结局包括 CHD 复合结局、所有 CVD 结局复合、卒中和心力衰竭（HF）以及死亡率。对基因型-治疗相互作用进行了检验。
有 38698 名参与者至少对纳入研究的一种多态性进行了基因分型。对于 MMP9 R668Q（rs2274756），与氨氯地平相比，氯噻酮治疗时 AA 受试者的大多数结局的风险比（HR）更低（例如，CCHD：GG = 1.00，GA = 1.01，AA = 0.64；P = 0.038）。对于 MMP9 R279Q（rs17576），在 CHD 和复合 CVD 结局中观察到 MMP12 N122S 的适度药物遗传学发现。对于 MMP12 N122S（rs652438），携带至少一个 G 等位基因且接受氯噻酮治疗的患者的 CHD 风险较低（CHD：AA = 1.07，AG = 0.80，GG = 0.49；P = 0.005）。在赖诺普利-氨氯地平的比较中，至少携带一个 MMP12 N122S 位点 G 等位基因的参与者的 HR 更高（CHD：AA = 0.94，AG = 1.19，GG = 1.93；P = 0.041）。对于 MMP12-82A>G（rs2276109），主要结局未发现药物遗传学效应，尽管氯噻酮-氨氯地平比较中 AA 纯合子的 HF 风险较低（P = 0.015）。
我们观察到降压药物与 MMP9 和 MMP12 之间的 CHD 和复合 CVD 相互作用。数据表明，这些基因可能为治疗决策提供有用的临床信息。
