Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting

Natarajan, P. et al. (2017) Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation, 135(22), pp. 2091-2101. (doi:10.1161/CIRCULATIONAHA.116.024436) (PMID:28223407)

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Abstract

Background—Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of two randomized controlled primary prevention trials (ASCOT and JUPITER), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we sought to confirm this observation in a third primary prevention randomized controlled trial. Additionally, we assessed if 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, n=4,910) and two observational cohort studies (CARDIA and BioImage, n=1,154 and 4,392). For each participant, we calculated a polygenic risk score (PRS) derived from up to 57 common DNA sequence variants previously associated with coronary heart disease (CHD). We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of PRS) versus all others (WOSCOP)S as well as the association between the PRS 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% CI, 22%-60%; P < 0.001) whereas in all others, relative risk reduction was 24% (95% CI 8%-37%; P = 0.004) despite similar LDL 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 three 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 was 1.3% (95% CI, 0.6%-1.9%) in all others. Each standard deviation 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 CHD event.

Item Type:Articles
Additional Information:Funding: Dr. Natarajan is supported by the John S. LaDue Memorial Fellowship from Harvard Medical School. Dr. Kathiresan is supported by an Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital and grants from the NIH (HL127564 and UM1HG008895).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Young, Dr Robin and Sattar, Professor Naveed and Ford, Professor Ian
Authors: Natarajan, P., Young, R., Stitziel, N. O., Padmanabhan, S., Baber, U., Mehran, R., Sartori, S., Fuster, V., Reilly, D. F., Butterworth, A. S., Rader, D. J., Ford, I., Sattar, N., and Kathiresan, S.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Circulation
Publisher:American Heart Association
ISSN:0009-7322
ISSN (Online):1524-4539
Published Online:21 February 2017
Copyright Holders:Copyright © 2017 American Heart Association, Inc.
First Published:First published in Circulation 135(22): 2091-2101
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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