title: Genome-wide approach to identify novel candidate genes for beta blocker response in heart failure using an experimental model.
abstract: BACKGROUND
  We explored use of a canine model of heart failure (HF) for pharmacogenomic discovery, specifically analyzing response to beta blockers (BB).
  
  
  METHODS
  Dogs with HF that received BB (n=39) underwent genome-wide genotyping to test the association with changes in left ventricular (LV) volume and ejection fraction after treatment. Resulting candidate genes underwent RNA quantification in cardiac tissue from normal (n=5), placebo-HF (n=5), and BB-HF (n=7) dogs.
  
  
  RESULTS
  Three markers met whole-genome significance for association with improved LV end-systolic volume after BB therapy (each p<5 x 10(-7)). RNA quantification of three candidate genes near these markers -- GUCA1B, RRAGD, and MRPS10 -- revealed that gene expression levels in BB-HF dogs were between that of placebo-HF dogs and normal dogs.
  
  
  CONCLUSIONS
  Genome-wide pharmacogenomic screening in a canine model of HF suggests 3 novel BB response candidate loci. This approach is adaptable to discovering mechanisms of action for other drug therapies, and may be a useful strategy for identifying candidate genes for drug response in the pre-clinical setting.
authors.affiliation: Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Lanfear
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Sudhish
authors.initials: S
authors.lastname: Mishra
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics*; D010919:Placebos
chemical_list: D000319:Adrenergic beta-Antagonists; D010919:Placebos