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The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy

The Pharmacogenomics Journal volume 17, pages 204–208 (2017)Cite this article

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Abstract

Statins (HMG-CoA reductase inhibitors) lower low-density lipoprotein cholesterol (LDL-C) and prevent cardiovascular disease. However, there is wide individual variation in LDL-C response. Drugs targeting proprotein convertase subtilin/kexin type 9 (PCSK9) lower LDL-C and will be used with statins. PCSK9 mediates the degradation of LDL receptors (LDLRs). Therefore, a greater LDL-C response to statins would be expected in individuals with PCSK9 loss-of-function (LOF) variants because LDLR degradation is reduced. To examine this hypothesis, the effect of 11 PCSK9 functional variants on statin response was determined in 669 African Americans. One LOF variant, rs11591147 (p.R46L) was significantly associated with LDL-C response to statin (P=0.002). In the three carriers, there was a 55.6% greater LDL-C reduction compared with non-carriers. Another functional variant, rs28362261 (p.N425S), was marginally associated with statin response (P=0.0064).The effect of rs11591147 was present in individuals of European ancestry (N=2388, P=0.054). The therapeutic effect of statins may be modified by genetic variation in PCSK9.

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Acknowledgements

This study was supported by GM109145, UL1 RR024975, P50GM115305, U19HL065962, U01HL069757 and K23AR064768. This study was also supported by AHA 16SDG27490014. The data set(s) used for the analyses described were obtained from Vanderbilt University Medical Center's resources, BioVU and the Synthetic Derivative, which are supported by institutional funding and by the Vanderbilt National Center for Advancing Translational Science grant 2UL1 TR000445-06 from NCATS/NIH. Existing genotypes in BioVU were funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/NIGMS.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Q Feng & C M Stein

  2. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA

    W Q Wei, L Bastarache & J C Denny

  3. Division of Rheumatology, Department of Medicine, Vanderbilt University, Nashville, TN, USA

    C P Chung

  4. Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA

    R T Levinson

  5. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    C M Stein

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Correspondence to Q Feng.

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Feng, Q., Wei, W., Chung, C. et al. The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy. Pharmacogenomics J 17, 204–208 (2017). https://doi.org/10.1038/tpj.2016.3

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