TY - JOUR
T1 - Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure
AU - Perez, Marco V.
AU - Pavlovic, Aleksandra
AU - Shang, Ching
AU - Wheeler, Matthew T.
AU - Miller, Clint L.
AU - Liu, Jing
AU - Dewey, Frederick E.
AU - Pan, Stephen
AU - Thanaporn, Porama K.
AU - Absher, Devin
AU - Brandimarto, Jeffrey
AU - Salisbury, Heidi
AU - Chan, Khin
AU - Mukherjee, Rupak
AU - Konadhode, Roda P.
AU - Myers, Richard M.
AU - Sedehi, Daniel
AU - Scammell, Thomas E.
AU - Quertermous, Thomas
AU - Cappola, Thomas
AU - Ashley, Euan A.
N1 - Publisher Copyright:
© 2015 American College of Cardiology Foundation.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - HCRTR2
KW - Key Words genome-wide association study
KW - pharmacogenomics
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U2 - 10.1016/j.jacc.2015.09.061
DO - 10.1016/j.jacc.2015.09.061
M3 - Article
C2 - 26653627
AN - SCOPUS:84962229653
SN - 0735-1097
VL - 66
SP - 2522
EP - 2533
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -