Pharmacogenetic Determinants of Statin-Induced Reductions in C-Reactive Protein

• Published in: Circulation. Cardiovascular genetics Vol. 5; no. 1; pp. 58 - 65
• Main Authors: Chu, Audrey Y, Guilianini, Franco, Barratt, Bryan J, Nyberg, Fredrik, Chasman, Daniel I, Ridker, Paul M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.02.2012; Lippincott Williams & Wilkins
• Subjects: Apolipoproteins E - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; C-reactive protein; C-Reactive Protein - analysis; Cardiac and Cardiovascular Systems; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - genetics; cholesterol; cholesterol levels; Cholesterol, LDL - blood; coronary events; disease; Female; Fluorobenzenes - therapeutic use; gene; genetics; genome-wide association; Genome-Wide Association Study; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; inflammation; Kardiologi; lipid-lowering response; Male; Medical sciences; Neoplasm Proteins - genetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Pyrimidines - therapeutic use; Receptors, Lysophosphatidic Acid - genetics; Rosuvastatin Calcium; sequence; simvastatin; statins; Sulfonamides - therapeutic use; therapy; whole-genome; Pharmacogenetics; Acute phase protein; Reduction; C-reactive protein; statins; Genetics; Statin derivative; Inflammation; C reactive protein; Cholesterol; Antilipemic agent
• ISSN: 1942-325X; 1942-3268
• DOI: 10.1161/CIRCGENETICS.111.961847

BACKGROUND—In randomized trials, statins reduce plasma levels of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C), and the magnitude of event reduction relates to on-treatment levels of both. However, whether different mechanisms underlie statin-induced CRP and LDL-C reduction is unknown. METHODS AND RESULTS—We performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6766 participants of European ancestry randomly allocated to 20 mg/d of rosuvastatin or placebo in the JUPITER trial. Among 3386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy (P<0.001 for both) and essentially uncorrelated (r<0.03). No variants in the 3 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 associated with LDL-C reduction were associated with rosuvastatin-induced CRP change after multiple testing correction. Among candidate single-nucleotide polymorphisms 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=6.4×10) and with rs2847281 in PTPN2 (mean, 3.7% [SE, 1.9%] change in CRP per minor allele; P=7.4×10). 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 3380 placebo-allocated JUPITER participants. CONCLUSIONS—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.