Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting - PubMed (original) (raw)

Randomized Controlled Trial

. 2017 May 30;135(22):2091-2101.

doi: 10.1161/CIRCULATIONAHA.116.024436. Epub 2017 Feb 21.

Robin Young 1, Nathan O Stitziel 1, Sandosh Padmanabhan 1, Usman Baber 1, Roxana Mehran 1, Samantha Sartori 1, Valentin Fuster 1, Dermot F Reilly 1, Adam Butterworth 1, Daniel J Rader 1, Ian Ford 1, Naveed Sattar 1, Sekar Kathiresan 2

Affiliations

Randomized Controlled Trial

Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting

Pradeep Natarajan et al. Circulation. 2017.

Abstract

Background: 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.

Methods: 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).

Results: 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; P<0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; _P_=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 (P 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.

Conclusions: 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.

Clinical trial registration: 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.

Keywords: humans; hydroxymethylglutaryl-CoA reductase inhibitors; polymorphism, genetic; primary prevention; vascular calcification.

© 2017 American Heart Association, Inc.

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Figures

Figure 1

Figure 1. Incident Coronary Heart Disease Events by Statin Therapy and Genetic Risk Group in WOSCOPS

Nonfatal myocardial infarction or death from coronary heart disease rate by randomized treatment group and polygenic risk group in the WOSCOPS trial. Absolute events (and percentage) per individuals in each group is shown at the bottom of the bars. This represents 604 events over 64,031 total patient-years of follow up. The follow up period was 4.8 years (SD 0.7 years) within the trial for both placebo and statin groups, and out of trial was 8.1 years (SD 3.4 years) in the placebo group and 8.4 years (SD 3.0 years) in the statin-treated group.

Figure 2

Figure 2. Forest Plot of Incident Coronary Heart Disease After Statin Therapy by Genetic Risk Group in Statin Primary Prevention Trials

The multi-variable adjusted hazard ratios of incident coronary heart disease after statin therapy by genetic risk group are presented for three primary prevention trials. Data from JUPITER and ASCOT-LLA were obtained from prior analyses. Fixed effects meta-analysis was used to estimate the relative effect of statin therapy on incident coronary heart disease across trials for each genetic risk group (P for difference = 0.05). CI = confidence interval; HR = hazard ratio.

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