Differential Genetic Effects on Statin-Induced Changes Across Low-Density Lipoprotein-Related Measures

Abstract

Background: Statin therapy influences not only low-density lipoprotein (LDL) cholesterol levels but also LDL-related biomarkers, including non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total number of LDL particles, and mean LDL particle size. Recent studies have identified many genetic loci influencing circulating lipid levels and statin-induced LDL cholesterol reduction. However, it is unknown how these genetic variants influence statin-induced changes in LDL subfractions and non-HDL-C.

Methods and results: One hundred sixty candidate single-nucleotide polymorphisms for effects on circulating lipid levels or statin-induced LDL-cholesterol lowering were tested for association with response of LDL subfractions and non-HDL-C to rosuvastatin or placebo for 1 year among 7046 participants from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Of the 51 single-nucleotide polymorphisms associated with statin response for ≥ 1 of the LDL subfractions or non-HDL-C, 20 single-nucleotide polymorphisms could be clustered according to effects predominantly on LDL particle size, predominantly on LDL particle number, and on apolipoprotein B but not on LDL cholesterol or non-HDL-C.

Conclusions: These differential associations point to pathways of LDL response to statin therapy and possibly to mechanisms of statin-dependent cardiovascular disease risk reduction.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Keywords: NMR spectroscopy; cholesterol; genetics; genome-wide association study; lipoproteins, LDL; rosuvastatin.

© 2015 American Heart Association, Inc.

Figures

Figure 1

Dendrogram of 14 clusters from complete linkage hierarchical clustering and variance explained in rosuvastatin-induced absolute change for LDL cholesterol (LDL-C), non-HDL cholesterol (non-HDL-C), apolipoprotein B (apo B), LDL particle number (LDL-P), and LDL particle size (LDL-size) by candidate variants (p