title: Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure.
abstract: BACKGROUND
  The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function.
  
  
  OBJECTIVE
  This study sought to identify genetic variations associated with response to HF therapy.
  
  
  METHODS
  This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography.
  
  
  RESULTS
  Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10(-5)). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model.
  
  
  CONCLUSIONS
  A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Marco V
authors.initials: MV
authors.lastname: Perez
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pavlovic
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Ching
authors.initials: C
authors.lastname: Shang
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Wheeler
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Stephen
authors.initials: S
authors.lastname: Pan
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Porama K
authors.initials: PK
authors.lastname: Thanaporn
authors.affiliation: Hudson Alpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Brandimarto
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Heidi
authors.initials: H
authors.lastname: Salisbury
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Khin
authors.initials: K
authors.lastname: Chan
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Roda P
authors.initials: RP
authors.lastname: Konadhode
authors.affiliation: Hudson Alpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sedehi
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cappola
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California. Electronic address: euan@stanford.edu.
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D055106:Genome-Wide Association Study; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D064446:Orexin Receptors / Q000235:genetics*; D013318:Stroke Volume / Q000235:genetics*
chemical_list: C578626:HCRTR2 protein, human; C578628:Hcrtr2 protein, mouse; D064446:Orexin Receptors
keywords: HCRTR2; genome-wide association study; pharmacogenomics