NEW YORK (GenomeWeb) – Researchers from Stanford University and elsewhere have linked a gene previously associated with sleep to heart failure.
Stanford's Marco Perez and his colleagues performed a genome-wide association study to try to find out why some patients respond well to heart failure therapies while others do not.
"We have noticed some patients with heart failure who get medical therapy respond really nicely," Perez said in a statement. "Their heart function improves dramatically with medications. Whereas other patients, despite medical therapy, continue to worsen and require transplant."
Through genotyping of heart-failure patients who responded very well and very badly to therapy, combined with data from a large dataset on gene expression from human cardiac tissue, the researchers homed in on a variant in the regulatory region of the HCRTR2 gene that was associated with improved left ventricular function.
As they reported yesterday in the Journal of the American College of Cardiology, Perez and his colleagues recruited 866 patients from Stanford. They examined those whose ejection fraction improved by more than 20 percent while taking medication and those who exhibited no such improvement. The cases and controls were further matched for age, sex, race, and baseline ejection fraction, among others.
The team interrogated some 1,536 SNPs in each patient, including genic and intergenic SNPs as well as SNPs culled from network analyses and curated lists. They found that patients with the rs7767652 minor allele — which is situated about 2,700 base pairs upstream of HCRTR2 splice variant 1A — were less likely than transplant patients to have a more than 20 percent increase in ejection fraction.
The researchers then replicated their finding in 798 Caucasian patients from the Penn Heart Failure Study. They found that this minor allele is predicted to disrupt a transcription factor 4 binding site. In allele-specific gene expression assays using luciferase reporters in cell culture, they found that the minor allele construct led to lower luciferase activity as compared to the major allele.
They further noted that the minor allele disrupted d b-catenin/TCF4-mediated transactivation in cells overexpressing human b-catenin and TCF4 cofactor. Adding a TCF4 transactivation mutant, they noted, could abolish these effects.
Meanwhile, Perez and his colleagues found that HCRTR2 expression is higher in dilated cardiomyopathy and ischemic cardiomyopathy tissue samples as compared to controls, and that the HCRTR2 protein product was present in the diseased tissue and present in greater concentration in the left ventricle as compared to the right ventricle of the heart.
In a small cohort of mice, the researchers noted greater diastolic dysfunction in HCRTR2 TD mice as compared to wild-type mice, but no difference in systolic function. Further, mice treated with orexin A, an HCRTR2 agonist, had better systolic function as compared to controls given saline.
The HCRTR2 gene, the researchers said, encodes a G-coupled receptor that binds hypocretin (orexin) A and B, which are neuropeptides that help regulate appetite and sleep. The HCRTR2 gene in particular has been linked to narcolepsy.
Though there are well-known links between sleep disorders and heart failure, Perez said, "The exciting thing is that this gene is in a completely different neurohormonal axis — a completely different pathway than what has been looked at previously. Nobody had ever studied heart function in relation to this gene."
These findings also suggest that patients using long-term HCRTR2 antagonists might benefit from monitoring for heart failure symptoms, the researchers added.
"We already know that sleep apnea is bad for the heart," said Stanford researcher and senior author Euan Ashley in a statement. "One of the things we are now hoping to do is look at heart function in patients with narcolepsy."