Abstract 16018: Genetic Variation Near HCRTR2 Associates With Dramatic Improvement of Heart Function in Patients With Heart Failure
Background: The genetic predisposition to heart failure remains poorly characterized. Response to medical therapy is highly variable but may be influenced by genomic variation.
Methods: We screened 866 patients with heart failure and compared extremes of the distribution: patients with a dramatic response to medical therapy (n=29) compared to those who decompensated despite therapy requiring transplant (n=37) using a genome wide approach. We then developed a customized 1536 single nucleotide variant (SNV) array by combining a genome-wide association study with gene expression studies of heart failure tissue and semantic literature mining of Pubmed abstracts. In a larger heart failure group (n=591), we compared 136 patients with an absolute 10% improvement in left ventricular ejection fraction (LVEF) with 454 controls using our customized array. Replication was assessed in an independent heart failure cohort (n=797). Allele-specific luciferase reporter assays were used to measure effects of SNV on enhancer activity. Expression of our candidate gene was compared in human cardiomyopathic versus control tissue (n=350). Mice were exposed to candidate gene agonist plus angiotensin II and isoproterenol (Ag/Iso) and echocardiograms were performed.
Results: rs7767652, located immediately upstream of hypocretin (orexin) receptor 2 (HCRTR2), was associated with improvement in LVEF (OR 0.40, p=3.29x10-5).
Replication in the independent heart failure cohort demonstrated significant association between rs7767652 and LVEF. Reporter assays demonstrated higher relative enhancer activity with the rs7767652 major allele construct compared to the minor allele. Expression of HCRTR2 was significantly greater in human dilated cardiomyopathy (p=0.00017) and ischemic cardiomyopathy (p=0.000044) tissue compared to normal cardiac tissue.
Agonist(orexin)-exposed mice had worse ventricular function after Ag/Iso infusion compared to controls.
Conclusion: We identified and replicated an association between rs7767652 and improvement in LV function and demonstrated functional roles of this variant and its nearby gene.
Genomic variation near HCRTR2, a neuropeptide hormone receptor, may modulate the pharmacologic response to heart failure therapy.
- © 2013 by American Heart Association, Inc.