title: The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy.
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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: W Q
authors.initials: WQ
authors.lastname: Wei
authors.affiliation: Division of Rheumatology, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Chung
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Levinson
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bastarache
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Stein
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D015415:Biomarkers / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9