title: In search for genetic determinants of clinically meaningful differential cardiovascular event reduction by pravastatin in the PHArmacogenetic study of Statins in the Elderly at risk (PHASE)/PROSPER study.
abstract: BACKGROUND
  Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response.
  
  
  RESULTS
  We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease--PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n = 5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1 × 10(-4) were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n = 711) and WOSCOPS (n = 522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p = 0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing.
  
  
  CONCLUSIONS
  We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited.
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Netherlands Consortium for Healthy Ageing, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: i.postmus@lumc.nl.
authors.forename: Iris
authors.initials: I
authors.lastname: Postmus
authors.affiliation: Robertson Center for Biostatistics, University of Glasgow, United Kingdom. Electronic address: paul.johnson@glasgow.ac.uk.
authors.forename: Paul C D
authors.initials: PC
authors.lastname: Johnson
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Netherlands Consortium for Healthy Ageing, PO Box 9600, 2300 RC Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: s.trompet@lumc.nl.
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Netherlands Consortium for Healthy Ageing, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: craen@lumc.nl.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.affiliation: Netherlands Consortium for Healthy Ageing, PO Box 9600, 2300 RC Leiden, The Netherlands; Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: p.slagboom@lumc.nl.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Celera, Alameda, CA, United States. Electronic address: james.devlin@celera.com.
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.affiliation: Celera, Alameda, CA, United States. Electronic address: dov.shiffman@celera.com.
authors.forename: Dov
authors.initials: D
authors.lastname: Shiffman
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA, United States; Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, MA, United States. Electronic address: fsacks@hsph.harvard.edu.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Sacks
authors.affiliation: Department of Epidemiology and Public Health, University College Cork, Ireland. Electronic address: patricia.kearney@ucc.ie.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Kearney
authors.affiliation: Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, United Kingdom. Electronic address: david.j.stott@glasgow.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stott
authors.affiliation: Department of Pharmacology and Therapeutics, University College Cork, Ireland. Electronic address: brenbuck@ucc.ie.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom. Electronic address: Naveed.sattar@glasgow.ac.uk.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Robertson Center for Biostatistics, University of Glasgow, United Kingdom. Electronic address: ian.ford@glasgow.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Netherlands Consortium for Healthy Ageing, PO Box 9600, 2300 RC Leiden, The Netherlands; Leyden Academy of Vitality and Ageing, Leiden, The Netherlands. Electronic address: r.g.j.westendorp@lumc.nl.
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.affiliation: Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. Electronic address: j.w.jukema@lumc.nl.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D007391:International Cooperation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000008:administration & dosage*; D011446:Prospective Studies; D012044:Regression Analysis
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin
keywords: Cardiovascular diseases; GWAS; Pharmacogenetics; Statins