title: Ancestry and other genetic associations with plasma PCSK9 response to simvastatin.
abstract: OBJECTIVE
  Statins stimulate transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of the low-density lipoprotein receptor, thus blunting the cholesterol-lowering effects of statin treatment. Although there is interindividual variation in PCSK9 statin response, little is known about ancestral and other genetic factors that could contribute to this variation.
  
  
  METHODS
  We measured plasma PCSK9 levels before and after 6 weeks of treatment with 40 mg/day simvastatin in 901 participants of the Cholesterol and Pharmacogenetics clinical trial and tested phenotypic and genetic factors for correlation with PCSK9 statin response.
  
  
  RESULTS
  Statin-induced changes in plasma low-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B were all significantly correlated with statin-induced changes in PCSK9. A detailed examination of the associations of genetic ancestry with PCSK9 statin response revealed that Ashkenazi Jews had smaller statin-induced increases in PCSK9 levels than other self-reported Caucasians (P=0.016). Using genomewide association analysis, we found that the 'G' minor allele of rs13064411 in the WD repeat domain 52 (WDR52) gene was significantly associated with greater statin-induced increases in plasma PCSK9 in Caucasians (P=8.2 × 10(-8)) in the Cholesterol and Pharmacogenetics trial.
  
  
  CONCLUSIONS
  Overall, these results suggest that genetic ancestry and the rs13064411 genotype contribute to interindividual variation in PCSK9 statin response in Caucasians.
authors.affiliation: aChildren's Hospital Oakland Research Institute, Oakland bLos Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Theusch
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
mesh_terms: D003598:Cytoskeletal Proteins; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D010447:Peptide Hydrolases; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D044469:Racial Groups / Q000208:ethnology / Q000235:genetics*; D057566:Self Report; D012697:Serine Endopeptidases / Q000097:blood*; D019821:Simvastatin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D019821:Simvastatin; C000601580:CFAP44 protein, human; D010447:Peptide Hydrolases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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