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J Am Coll Cardiol. 2015 Dec 8;66(22):2522-33. doi: 10.1016/j.jacc.2015.09.061.

Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure.

Author information

1
Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California.
2
Hudson Alpha Institute for Biotechnology, Huntsville, Alabama.
3
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina.
5
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina.
6
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
7
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
8
Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California. Electronic address: euan@stanford.edu.

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.

OBJECTIVES:

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.

KEYWORDS:

HCRTR2; genome-wide association study; pharmacogenomics

PMID:
26653627
DOI:
10.1016/j.jacc.2015.09.061
[Indexed for MEDLINE]
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