Two novel genetic loci identified that influence LDL-c response to statin therapy

Literature - Postmus I et al., Nat Commun. 2014

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Postmus I, Trompet S, Deshmukh HA, et al.,
Nat Commun. 2014 Oct 28;5:5068. doi: 10.1038/ncomms6068


Interindividual variability exists in the response to statins, both with regard to their LDL-c lowering capacity and the efficacy in reducing major cardiovascular events [1]. It has been suggested that some of this variability may be due to pharmacogenetic variation, which is supported by the identification of genetic variants associated with differential LDL-c response to statin treatment [2-4].
Some genome-wide association studies (GWAS) have identified loci associated with statin response [JUPITER, CARDS, ASCOT, 5-7], while others did not find genetic determinants of LDL-c response to statin therapy [4,8]. To date, the only consistently identified genetic variants that are associated with LDL-c response tot statin therapy are located at or around APOE or LPA. The Genomic Investigation of Statin Therapy (GIST) consortium was formed, in order to conduct a pharmacogenetic meta-analysis using GWAS data sets from randomised controlled trials (6) and observational studies (10). All studies independently performed a GWAS among statin users, examining the difference between on- and off-treatment natural log-transformed LDL-c levels.

Main results

  • In the first-stage meta-analysis, in data from up to 18.596 individuals, three loci and 13 single nucleotide polymorphisms (SNPs) were identified that attained genome-wide significance (P<5x10-8) for association with LDL-c response to treatment.
  • SNPs in APOE and LPA were confirmed, which showed the most significant associations, implying that carriers of these SNPs respond to statins with an additional 4.3% increase in LDL-c lowering per APOE allele and 5.9% smaller LDL-c lowering effect with LPA as compared with non-carriers.
  • In a second-stage meta-analysis, 246 SNPs with P<5x10-4 from 158 loci were further studied in three additional studies, with over 22.000 statin-treated subjects. This analysis revealed that carriers of a SNP in SORT1/CELSR2/PSRC1 have a 1.5% increase per allele in LDL-c lowering effect, while carriers of a SLCO1B1 SNP show 1.6% smaller LDL-c lowering per minor allele as compared with non-carriers.
  • LDL subfraction analyses showed that the SORT1 SNP minor allele was associated with greater statin-induced changes in all subfractions (large, medium, small and very small). The APOE, SLCO1B1, and LPA SNPs did not show significant associations with statin-induced changes in subfractions.
  • Additional statistical analyses suggest that genetic associations with baseline LDL-c had no or only little influence on the observed LDL response to statin treatment.
  • Functional and pathway analysis by means of a range of bioinformatics tools, suggests a strong biological and functional role in statin response for some of the identified gene loci, including APOE/TOMM40/PVRL2 and SORT1/CELSR2/PSRC2.


This study identified four loci at genome-wide significance for variation in LDL-c lowering in response to statin treatment. Two loci, APOE and LPA had previously been reported, while SORT1/CELSR2/PSRC1 and SLCO1B1i are newly identified. Different directional associations of the SNPs with statin-induced LDL changes were observed.

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1. Mangravite, L. M., Thorn, C. F. & Krauss, R. M. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J. 6, 360–374 (2006).
2. Postmus, I. et al. Pharmacogenetics of statins: achievements, whole-genome analyses and future perspectives. Pharmacogenomics 13, 831–840 (2012).
3. Chasman, D. I. et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 291, 2821–2827 (2004).
4. Hopewell, J. C. et al. Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study. Eur. Heart J. 34, 982–992 (2013).
5. Chasman, D. I. et al. Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ. Cardiovasc. Genet. 5, 257–264 (2012).
6. Deshmukh, H. A. et al. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J. Lipid Res. 53, 1000–1011 (2012).
7. Barber, M. J. et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS ONE 5, e9763 (2010).
8. Thompson, J. F. et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circ. Cardiovasc. Genet. 2, 173–181 (2009).

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