Pharmacogenetic determinants of statin-induced reductions in C-reactive protein.
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.


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(2)<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(-4)) and with rs2847281 in PTPN2 (mean, 3.7% [SE, 1.9%] change in CRP per minor allele; P=7.4×10(-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 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.
Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215, USA. aychu@partners.org
Audrey Y
AY
Chu
Franco
F
Guilianini
Bryan J
BJ
Barratt
Fredrik
F
Nyberg
Daniel I
DI
Chasman
Paul M
PM
Ridker
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002097:C-Reactive Protein / Q000032:analysis*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005464:Fluorobenzenes / Q000627:therapeutic use*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000627:therapeutic use*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009363:Neoplasm Proteins; D011743:Pyrimidines; D049368:Receptors, Lysophosphatidic Acid; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D002097:C-Reactive Protein