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Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting
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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.
Clinical Trial registration
WOSCOPS was carried out and completed prior to the requirement for clinical trial registration. BioImage: NCT00738725 ( https://www.clinicaltrials.gov/ct2/show/NCT00738725). CARDIA: NCT00005130 ( https://clinicaltrials.gov/ct2/show/NCT00005130).