Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
Methods and results We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10−4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10−8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
Conclusions Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
- Genome-wide association study
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IP, HRW, ST, JWJ, JIR and RMK contributed equally.
↵†Passed away 17 January 2016.
Contributors Writing and analysis group: IP, HRW, ST, BJA, DIC, HAD, XL, RAJS, GKH, PBM, MJC, HMC, LAC, GH, CNAP, BMP, CMS, JWJ, JIR, RMK. IP and ST performed quality control on the individual study summary results. IP and ST performed meta-analysis. IP, HRW and RAJS performed additional analyses. All analysis and writing group authors extensively discussed the analysis, results, interpretation and presentation of results. All authors contributed to the research and reviewed the manuscript. Study concept and design of contributing studies: (PROSPER) JWJ, DJS, BMB, IF, NS, RGJW; (ASCOT) MJC, PS, NP, AS, DCS, EO; (CARDS) HAD, HMC, PMM, JB, PND, AN, GH; (PARC) XL, YDIC, JIR, RMK; (TNT) JJPK; (AGES) LJL, TBH, VG; (ARIC) CLA, EAW, TS, EB, CMB; (BioVU) QPF, WQW, CMS, RAW, JCD; (CHS, HVH) NS, KR, TL, BMP; (FHS) LAC, RSV; (HABC) SRC, YL; (MESA) XG, SRH, WP, JIR, SSR; (Rotterdam Study) CEK, BHS, AGU, AH, FR; (JUPITER) DIC, BJB, FN, PMR; (GoDARTS) CNAP, HMC. Phenotype data acquisition of contributing studies: (PROSPER) JWJ, DJS, BMB, IF, AJMC, NS, RGJW; (ASCOT) MJC, PBM, PS, NP, AS, DCS, EO, SSH; (CARDS) HAD, HMC, PMM, JB, PND, AD, GH; (PARC) XL, YDIC, JIR, RMK; (TNT) JJPK; (AGES) GE; (ARIC) CMB; (BioVU) WQW, CMS; (CHS, HVH) KLW, JCB, AMA, NLS, BMP; (FHS) LAC, CJO, RSV; (GoDARTS) CNAP, HMC; (HABC) SRC; (MESA) SRH, JIR; (Rotterdam Study) CEK, BHS, AH, OHF; (JUPITER) DIC, PMR. Genotype data acquisition of contributing studies: (PROSPER) ST, JWJ, AJMC, PES; (ASCOT) MJC, HRW, PBM, PS, AS, SSH; (CARDS) HAD, HMC, PMM, PND, AN, GH; (PARC) YDIC, JIR, DAN, JDS; (TNT) BJA, MPD, SMB, GKH, JCT; (AGES) AVS; (ARIC) EB; (BioVU) QPF, JCD, CTL; (CHS, HVH) JCB; (FHS) CJO; (GoDARTS) CNAP, HMC; (HABC) YL; (MESA) KDT, JIR; (Rotterdam Study) AGU, FR; (JUPITER) DIC, BJB, FN, PMR. Primary analysis from contributing studies: (PROSPER) IP, ST, AJMC, RAJS, PES; (ASCOT) HRW, MRB; (CARDS) HAD, HMC, PMM; (PARC) XL, YDIC, JIR; (TNT) BJA, MPD, SMB, GKH, JCT; (AGES) AVS; (ARIC) CLA, EAW, TS; (BioVU) QPF, WQW, CTL; (CHS, HVH) KLW, KR, TL; (FHS) LAC, FS; (GoDARTS) CNAP, HMC; (HABC) DSE, JMS; (MESA) KDT, XG, JIR; (Rotterdam Study) CEK, BHS; (JUPITER) DIC.
Competing interests BMP serves on the Data and Safety Monitoring Board of a clinical trial funded by the device manufacturer (Zoll LifeCor) and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. NP and AS received funding from Pfizer for the extended follow-up of the ASCOT UK participants. DIC and PMR received research support for independent genetic analysis in JUPITER from AstraZeneca. FN and BJB have employment, stock and stock options in AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics such as rosuvastatin, but do not consider that this creates any conflict of interest with the subject-matter of this publication. RMK serves on the Merck Global Atherosclerosis Advisory Board.
Patient consent Obtained.
Ethics approval All studies were performed with the approval of the Local Medical Ethics Committees.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Summary data are available upon request by the corresponding author.
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