Abstract
BackgroundElevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF.MethodsPatients who met Framingham criteria for HF and had an ejection fraction < 50% were prospectively enrolled in a genetic HF registry (2007–2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant “hits” (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX).ResultsThe cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 × 10−8). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population.ConclusionsThese data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts.
Highlights
Heart failure (HF) remains a considerable public health problem, with an estimated 5.7 million people living with heart failure (HF) in the USA, resulting in > 1 million HF hospitalizations and > $30 billion in health care costs annually [1]
The association with heart rate (HR) for four of these Single nucleotide polymorphisms (SNP) were replicated in our study, with P values ranging from 2.55 × 10−4 to 7.75 × 10−5 (Bonferroni corrected critical P value threshold 1.16 × 10−3)
All four of these SNPS were within a single region of chromosome 6, within the gene GJA1 which encodes connexin 43
Summary
Heart failure (HF) remains a considerable public health problem, with an estimated 5.7 million people living with HF in the USA, resulting in > 1 million HF hospitalizations and > $30 billion in health care costs annually [1]. Observational and interventional studies in adults demonstrate that elevated heart rate (HR) is a modifiable risk factor in patients with HF [3,4,5,6]. Beta-blockers represent one of Previous studies have examined genetic factors influencing HR in various settings. In the context of beta-blocker (BB) therapy, GRK5 was suspected of influencing this but in one study showed no association of GRK5 genotype with heart rate [9]. The overall goal of this study was to test the validity of previous candidate gene associations and to identify novel genetic determinants of HR in a diverse cohort of HFrEF patients via GWAS. Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
