title: Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses.
abstract: BACKGROUND
  The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.
  
  
  METHODS
  The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.
  
  
  RESULTS
  Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.
  
  
  CONCLUSIONS
  With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.
authors: Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. s.trompet@lumc.nl
authors: Stella
authors: S
authors: Trompet
authors: Anton J M
authors: AJ
authors: de Craen
authors: Iris
authors: I
authors: Postmus
authors: Ian
authors: I
authors: Ford
authors: Naveed
authors: N
authors: Sattar
authors: Muriel
authors: M
authors: Caslake
authors: David J
authors: DJ
authors: Stott
authors: Brendan M
authors: BM
authors: Buckley
authors: Frank
authors: F
authors: Sacks
authors: James J
authors: JJ
authors: Devlin
authors: P Eline
authors: PE
authors: Slagboom
authors: Rudi G J
authors: RG
authors: Westendorp
authors: J Wouter
authors: JW
authors: Jukema
mesh_terms: D000368:Aged; D055106:Genome-Wide Association Study; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008077:Lipoproteins, LDL / Q000097:blood / Q000235:genetics*; D010597:Pharmacogenetics; D010919:Placebos; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use; D011446:Prospective Studies
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D010919:Placebos; D017035:Pravastatin