Abstract
Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10−4 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10−8). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.
Highlights
Therapy with statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, is widely used for the primary and secondary prevention of cardiovascular disease (Cholesterol Treatment Trialists et al, 2015)
In addition to many smaller pharmacogenetic studies, a large genome-wide association study (GWAS), which investigated the genetic variation associated with the LDL cholesterol lowering response of statins identified four independent loci mapped to the APOE, LPA, SORT1, SCLO1B1 genes (Postmus et al, 2014a)
While many pharmacogenetic studies have investigated the effect of statins on LDL-cholesterol lowering response, the pharmacogenetic effect on cardiovascular risk reduction in response to statin treatment has been studied in small candidate gene studies with limited success (Peters et al, 2008; Peters et al, 2010a; Peters et al, 2010b; Peters et al, 2011; Leusink et al, 2014; Li et al, 2015)
Summary
Therapy with statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, is widely used for the primary and secondary prevention of cardiovascular disease (Cholesterol Treatment Trialists et al, 2015). While many pharmacogenetic studies have investigated the effect of statins on LDL-cholesterol lowering response, the pharmacogenetic effect on cardiovascular risk reduction in response to statin treatment has been studied in small candidate gene studies with limited success (Peters et al, 2008; Peters et al, 2010a; Peters et al, 2010b; Peters et al, 2011; Leusink et al, 2014; Li et al, 2015). Candidate gene studies into lipid lowering pathways might not capture all main pharmacogenetic effects responsible for the differential response to statin therapy with respect to cardiovascular events (Leusink et al, 2016). In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction
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