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

Background

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.

Conclusion

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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