Pharmacogenetic Determinants of Statin-Induced Reductions in C-Reactive Protein
Do different mechanisms underlie statin-induced C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C) reduction?
The authors performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6,766 participants of European ancestry randomly allocated to 20 mg/day of rosuvastatin or placebo in the JUPITER trial.
Among 3,386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy (both p values < 0.001) and essentially uncorrelated (r2 < 0.03). None of the three genes (ABCG2, LPA, and APOE) that previously showed genome-wide association with LDL-C reduction in this cohort and none of the candidate single nucleotide polymorphisms (SNPs) associated with LDL-C reduction were associated with rosuvastatin-induced CRP change after multiple testing correction. Among candidate SNPs selected from prior genetic analyses of baseline CRP, CRP reduction was associated with rs2794520 in CRP (mean -3.5% [se = 2.0] change in CRP per minor allele, p = 6.4 x 10–4), and with rs2847281 in PTPN2 (mean 3.7% [se = 1.9] change in CRP per minor allele, p = 7.4 x 10–4). These associations remained significant after multiple testing correction, but were not significant in a formal test of interaction. Neither variant was associated with rosuvastatin-induced LDL-C reduction or with CRP reduction among 3,380 placebo-allocated JUPITER participants.
The genetic determinants of rosuvastatin-induced CRP reduction differ from, and are largely independent of, the major pharmacogenetic determinants of rosuvastatin-induced LDL-C reduction. This supports the hypothesis that differing pathways may mediate the anti-inflammatory and lipid-lowering properties of statin therapy.
There is clinical trial evidence that the reduction in cardiovascular event rate in placebo-controlled primary and secondary coronary heart disease prevention trials with atorvastatin, pravastatin, and rosuvastatin is related to both magnitude of reduction in LDL-C and achieving a high-sensitivity CRP <1 mg/L. Based on this study, the degree to which different statins influence the genetic determinants of CRP and immune function may impact their clinical efficacy independent of lipid-lowering effect, a posit not accepted by many.
Keywords: Fluorobenzenes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Vascular Diseases, Genome-Wide Association Study, Pyrimidines, Coronary Disease, Heptanoic Acids, Pyrroles, Cholesterol, C-Reactive Protein, Polymorphism, Single Nucleotide, Pravastatin, Pharmacogenetics, Sulfonamides
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