Human Heart Rate

Abstract

Objective To understand the role of genetic variation in the catecholamine biosynthetic pathway for control of human heart rate (HR). Background Human HR is an integrated cardiovascular trait predictive of morbidity and survival. Since the autonomic pathway exerts rapid control over the heart, we probed the role of heredity in control of HR, focusing on a component of the autonomic sympathetic pathway already predictive of outflow responses: Cytochrome b561 (CYB561), the electron shuttle in catecholamine vesicle membranes for transmitter biosynthesis. Methods We studied hereditary control of HR with the twin pair design, at rest and during environmental (cold) stress. SNP disruption of a micro-RNA recognition motif in the human CYB561 3’-UTR was identified computationally, and its differential effect on gene expression was demonstrated in a transfected luciferase reporter / 3’-UTR variant. We exposed of stem-cell-derived human embryoid bodies to the micro-RNA mimic or antagomir oligonucleotides, and observed effects on contraction rate in proto-hearts. Results Substantial heritability (h2) was demonstrated, by twin pair variance components, for both basal/resting HR (h2=50.9±6.4% of trait variation, p=2.47E-10) and stress-augmented HR (h2=55.1±5.9%, p=8.79E-13), and the two HR traits shared genetic determination (genetic covariance ρG=0.747±0.058, p=2.85E-09). CYB561 displayed one common genetic variant in the transcript region: A+1485G (rs3087776), in the 3’-UTR, 1485 bp downstream of the termination codon, in a conserved region, with the A-allele ancestral in primates. In a twin/sibling sample (n=576), A+1485G influenced HR, both at rest (p=0.010) and after environmental stress (p=0.002), with the minor (A) allele displaying a recessive effect with lower HR. The effect of A+1485G on HR was extended by meta-analysis into two additional population samples (total n=2579), and the influence remained directionally consistent and significant (p=0.007). A+1485G disrupted a micro-RNA (hsa-miR-1294) recognition motif in the 3’-UTR (with AG) was demonstrated in a transfected luciferase reporter / human 3’-UTR variant system in two different neuronal/neuroendocrine cell types, and the micro-RNA effect was further documented by co-transfection of a hsa-miR-1294 mimic, yielding an exaggerated decline in expression of the A-allele (better match) reporter (p=4.3E-05). Similar findings of differential 3’-UTR allelic susceptibility to miR-1294 were noted during expression of the full-length human CYB561 mRNA with its cognate 3’-UTR. Finally, exposure of stem-cell-derived human embryoid bodies to miR-1294 mimic or antagomir oligonucleotides yielded directionally opposite effects on contraction rate in proto-hearts. Conclusions HR is a substantially heritable trait, with genetic influence by variation in the adrenergic pathway, here shown for mRNA translational control at the CYB561 step of transmitter formation. The results have implications for potentially modifiable autonomic pathways that influence this risk trait i...

Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study

“…However, genetic correlations for RMSSD and HR between the stress conditions appeared to be smaller than the genetic correlations between rest and stress suggesting that there is less overlap of genes influencing HR and RMSSD between the two stress conditions than between rest and stress. Comparatively, the genetic correlation between HR during rest and CPT was 0.79 in our study and with 0.75 very similar in a twin study by Zhang et al [ 35 ].…”

“…This is similar to the family study by Singh et al [ 17 ] who also found resting HR heritability to be moderately higher compared with high frequency, low frequency, VLF, total power, and SDNN. However, our resting, WCT and CPT HR heritability estimates are lower compared with those typically found by twin studies during rest and both mental and physical stress [ 22 , 35 ]. This could be because of the different study design, their smaller population, and/or ethnically mixed sample size.…”

Genomics of Cardiovascular Measures of Autonomic Tone

“…(78) A total of 40% of the variability in HR change in response to cold pressor test was found to be heritable in a study of 576 individuals from twin and sibling pairs. (79) Another study found that 12–25% of the blood pressure response to cold pressor test was due to genetic effects in a family cohort of 835 individuals. (80)…”

“…(84) Multiple variants within sympathetic pathway have been associated with differential response to the cold pressor test (Table 2). Amongst those are variants in the CYB561 gene, a transporter gene in the sympathetic pathway,(79) as well as variants in the tyrosine hydroxylase ( TH ) gene, involved in catecholamine biosynthesis. (85) Polymorphism in the beta-2 adrenergic receptor was also associated with the blood pressure response in a cohort of young twins.…”

Interpreting the various associations of MiRNA polymorphisms with susceptibilities of cardiovascular diseases

“…[8–10] MiRNAs were proved to regulate several core pathways in guiding coronary artery biogenesis, cardiomyocytes regeneration, hypertrophy, and function maintaining. [9,11–13] Given the important role of miRNAs in CVDs, they are being exploited for diagnosis, prevention, and treatment of CVD.…”