Natarajan Pradeep, Young Robin, Stitziel Nathan O, Padmanabhan Sandosh, Baber Usman, Mehran Roxana, Sartori Samantha, Fuster Valentin, Reilly Dermot F, Butterworth Adam, Rader Daniel J, Ford Ian, Sattar Naveed, Kathiresan Sekar
From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
Circulation. 2017 May 30;135(22):2091-2101. doi: 10.1161/CIRCULATIONAHA.116.024436. Epub 2017 Feb 21.
Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis.
We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage).
Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; <0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; =0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others ( for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque.
Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.
他汀类药物治疗的相对风险降低在几乎所有迄今研究的亚组中都是一致的。然而，在两项随机对照一级预防试验（ASCOT[盎格鲁-斯堪的纳维亚心脏结局试验-降脂组]和JUPITER[他汀类药物在预防中的应用：一项评估瑞舒伐他汀的干预试验]）的分析中，他汀类药物治疗在高遗传风险亚组中导致了更大的相对风险降低。在此，我们旨在通过第三项一级预防随机对照试验来证实这一观察结果。此外，我们评估了高遗传风险人群是否有更大的亚临床冠状动脉粥样硬化负担。
我们研究了来自一项他汀类药物治疗一级预防随机对照试验（WOSCOPS[苏格兰西部冠心病预防研究]；n = 4910）以及两项观察性队列研究（CARDIA[青年成人冠状动脉风险发展研究]和BioImage；分别为n = 1154和4392）的参与者。对于每位参与者，我们计算了一个多基因风险评分，该评分源自多达57个先前与冠心病相关的常见DNA序列变异。我们比较了他汀类药物治疗在高遗传风险人群（多基因风险评分最高五分位数）与所有其他人群（WOSCOPS）中的相对疗效，以及多基因风险评分与冠状动脉钙化（CARDIA）和颈动脉斑块负担（BioImage）之间的关联。
在WOSCOPS试验中，高遗传风险参与者接受他汀类药物治疗后，相对风险降低了44%（95%置信区间[CI]，22 - 60；<0.001），而在所有其他参与者中，尽管低密度脂蛋白胆固醇降低程度相似，但相对风险降低了24%（95%CI，8 - 37；=0.004）。在对WOSCOPS、ASCOT和JUPITER一级预防进行的研究水平荟萃分析中，高遗传风险人群的相对风险降低为46%，而所有其他人群为26%（异质性P = 0.05）。在所有三项研究中，他汀类药物治疗在高遗传风险组中的绝对风险降低为3.6%（95%CI，2.0 - 5.1），在所有其他人群中为1.3%（95%CI，0.6 - 1.9）。多基因风险评分每增加1个标准差，发生冠状动脉钙化的可能性增加1.32倍（95%CI，1.04 - 1.68），颈动脉斑块负担增加9.7%（95%CI，2.2 - 17.8）。
高遗传风险人群有更大的亚临床动脉粥样硬化负担，并且从他汀类药物治疗预防首次冠心病事件中获得更大的相对和绝对益处。
