Abstract
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Highlights
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation
To search for genetic variants associated with differential low-density lipoprotein cholesterol (LDL-C) response to statin therapy, each study independently performed a genome-wide association studies (GWAS) among statin users, using the difference between the natural log-transformed LDL-C levels onand off-treatment as the response variable
The most significant association was for a single nucleotide polymorphisms (SNPs) on chromosome 19, at APOE (rs445925, minor allele frequency (MAF) 1⁄4 0.098, b 1⁄4 À 0.043, s.e. 1⁄4 0.005, P 1⁄4 1.58 Â 10 À 18; Fig. 2a), indicating that carriers of the rs445925 SNP respond to statins with an additional 4.3% increase per allele in LDL-C lowering effect compared with non-carriers
Summary
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. The suggestion that some of this variability may be due, in part, to common pharmacogenetic variation is supported by previous studies that have identified genetic variants associated with differential LDL-C response to statin therapy[4,5,6]. On the basis of these studies, as well as previous candidate gene studies[4,6], the only genetic variants that have been consistently identified to be associated with variation in LDL-C response to statin therapy, irrespective of statin formulation, are located at or nearby APOE and LPA. To determine whether additional loci may influence LDL-C response to statins, we formed the Genomic Investigation of Statin Therapy (GIST) consortium and conducted a pharmacogenetic meta-analysis using GWAS data sets from randomized controlled trials (RCTs) and observational studies. These findings will extend the knowledge of the pharmacogenetic architecture of statin response
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