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

Marco V. Perez, Aleksandra Pavlovic, Ching Shang, Matthew T. Wheeler, Clint L. Miller, Jing Liu, Frederick E. Dewey, Stephen Pan, Porama K. Thanaporn, Devin Absher, Jeffrey Brandimarto, Heidi Salisbury, Khin Chan, Rupak Mukherjee, Roda P. Konadhode, Richard M. Myers, Daniel Sedehi, Thomas E. Scammell, Thomas Quertermous, Thomas Cappola & 1 others Euan A. Ashley

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2522-2533
Number of pages12
JournalJournal of the American College of Cardiology
Volume66
Issue number22
DOIs
StatePublished - 2015
Externally publishedYes

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Genomics
Heart Failure
Orexin Receptors
Alleles
Echocardiography
Odds Ratio
human HCRTR2 protein
Exercise
Therapeutics
Systems Analysis
Luciferases
Left Ventricular Function
Tachycardia
Genes
Cicatrix
Nucleotides
Genotype
Alcohols
Genome
Gene Expression

Keywords

  • HCRTR2
  • Key Words genome-wide association study
  • pharmacogenomics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Perez, M. V., Pavlovic, A., Shang, C., Wheeler, M. T., Miller, C. L., Liu, J., ... Ashley, E. A. (2015). Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure. Journal of the American College of Cardiology, 66(22), 2522-2533. https://doi.org/10.1016/j.jacc.2015.09.061

Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure. / Perez, Marco V.; Pavlovic, Aleksandra; Shang, Ching; Wheeler, Matthew T.; Miller, Clint L.; Liu, Jing; Dewey, Frederick E.; Pan, Stephen; Thanaporn, Porama K.; Absher, Devin; Brandimarto, Jeffrey; Salisbury, Heidi; Chan, Khin; Mukherjee, Rupak; Konadhode, Roda P.; Myers, Richard M.; Sedehi, Daniel; Scammell, Thomas E.; Quertermous, Thomas; Cappola, Thomas; Ashley, Euan A.

In: Journal of the American College of Cardiology, Vol. 66, No. 22, 2015, p. 2522-2533.

Research output: Contribution to journalArticle

Perez, MV, Pavlovic, A, Shang, C, Wheeler, MT, Miller, CL, Liu, J, Dewey, FE, Pan, S, Thanaporn, PK, Absher, D, Brandimarto, J, Salisbury, H, Chan, K, Mukherjee, R, Konadhode, RP, Myers, RM, Sedehi, D, Scammell, TE, Quertermous, T, Cappola, T & Ashley, EA 2015, 'Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure', Journal of the American College of Cardiology, vol. 66, no. 22, pp. 2522-2533. https://doi.org/10.1016/j.jacc.2015.09.061
Perez, Marco V. ; Pavlovic, Aleksandra ; Shang, Ching ; Wheeler, Matthew T. ; Miller, Clint L. ; Liu, Jing ; Dewey, Frederick E. ; Pan, Stephen ; Thanaporn, Porama K. ; Absher, Devin ; Brandimarto, Jeffrey ; Salisbury, Heidi ; Chan, Khin ; Mukherjee, Rupak ; Konadhode, Roda P. ; Myers, Richard M. ; Sedehi, Daniel ; Scammell, Thomas E. ; Quertermous, Thomas ; Cappola, Thomas ; Ashley, Euan A. / Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure. In: Journal of the American College of Cardiology. 2015 ; Vol. 66, No. 22. pp. 2522-2533.
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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.",
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author = "Perez, {Marco V.} and Aleksandra Pavlovic and Ching Shang and Wheeler, {Matthew T.} and Miller, {Clint L.} and Jing Liu and Dewey, {Frederick E.} and Stephen Pan and Thanaporn, {Porama K.} and Devin Absher and Jeffrey Brandimarto and Heidi Salisbury and Khin Chan and Rupak Mukherjee and Konadhode, {Roda P.} and Myers, {Richard M.} and Daniel Sedehi and Scammell, {Thomas E.} and Thomas Quertermous and Thomas Cappola and Ashley, {Euan A.}",
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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.

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.

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