Abstract
Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.
Highlights
Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), are widely prescribed to reduce low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events
Overall we observed 79 single nucleotide polymorphisms (SNPs) that were nominally (P,1024) associated with differential event reduction by pravastatin therapy (Table 2). These 79 SNPs clustered in 45 loci, where a locus is defined by associated SNPs that were within 100 kb of each other
The 45 loci were all .300 kb apart or on different chromosomes. None of these SNPs was in or near a gene that had been previously reported to be associated with coronary heart disease (CHD), involved in cholesterol metabolism, or involved in pravastatin metabolism
Summary
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), are widely prescribed to reduce low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. In an analysis of 14 randomized clinical trials, statin therapy was associated with about 20% reduction of major cardiovascular events for each mmol/L (38.7 mg/dL) reduction of LDL-C [1]. Statins are the most prescribed class of drugs and therapy is generally associated with LDL cholesterol lowering of 22–34%, individual variability in response to statin therapy has been noted. Multiple studies investigated whether genetic variants are associated with differential LDL-C reduction by statin therapy [4]. Evidence from several studies [5,6,7] suggests that the e3 allele of APOE is associated with differential LDL-C lowering by statin therapy. Variants of the HMGCR gene have been been shown to be associated with differential LDL-C reduction by statin treatment [6,8,9]. Several studies have reported an association between a KIF6 variant (rs20455) and differential event reduction by pravastatin [10,11] or intensive atorvastatin therapy [12], others found no association between rs20455 and differential event reduction from simvastatin [13] or rosuvastatin therapy [14]
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