Adrenergic Receptor Polymorphisms Associated with Resting Heart Rate: The HyperGEN Study

Wilk, Jemma B.; Myers, Richard H.; Pankow, James S.; Hunt, Steven C.; Leppert, M.; Freedman, Barry I.; Province, Michael A.; Ellison, R. Curtis

doi:10.1111/j.1469-1809.2005.00258.x

Cited by 28 publications

(19 citation statements)

References 21 publications

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“…Since increased sympathetic tone may contribute to HR elevation (3), and “tagging” genetic variation at the CYB561 locus may predict responses to pre-synaptic stimulation in humans (4), here we examined the association of sympathetic pathway gene CYB561 with HR traits, focusing on functional (rather than simply “tagging”) genetic variation. Already, it was known that genetic variation across the adrenergic pathway – GCH1 (5), TH (6), DBH (7), PNMT (8), and ADRB1 (9) – predicted control of HR; thus, we focused here on CYB561 . We found that common genetic variation in the CYB561 was confined to the 3’-UTR at A+1485G, which disrupted a micro-RNA recognition motif.…”

Section: Discussionmentioning

confidence: 99%

“…The role of heredity in control of HR has not been exhaustively examined, but genetic variation in the sympathetic pathway, including “tagging” (intronic) variation at the cytochrome b561 ( CYB561 ) locus reportedly influences cardiovascular responses to sympathetic activation (4). Indeed, naturally occurring genetic variation at every other point in the adrenergic pathway – GCH1 (5), TH (6), DBH (7) , PNMT (8) , and ADRB1 (9) – has already been associated with altered HR control, yet the interaction of CYB561 and HR is still unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Human Heart Rate

Zhang

Deacon

Rao

et al. 2014

Journal of the American College of Cardiology

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human Heart Rate

Zhang

Deacon

Rao

et al. 2014

Journal of the American College of Cardiology

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“…More than 50 genes associated with heart rhythm have been identified in mice [25], and differences by sex and strain of animals have also been found [26]. In the HyperGEN Study, Wilk et al [27] found that the proportion of variance in resting heart rate explained by genetic factors was 24% in African-Americans and 27% for whites. Given this evidence for epistasis in the endophenotype of heart rate and given the number of endophenotypes that may be involved in sustained blood pressure elevation, it is little wonder that genome wide association studies of hypertension have been difficult to replicate.…”

Section: Discussionmentioning

confidence: 99%

AGT M235T Genotype/Anxiety Interaction and Gender in the HyperGEN Study

et al. 2010

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BackgroundBoth anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups.MethodologyThe interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style).Principal FindingsAlthough there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype.Conclusion/SignificanceThe results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors.

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“…Several studies have tested these variants with various CV phenotypes, including blood pressure (BP) 15 , heart rate 16 , dilated cardiomyopathy 17 and composite CV outcomes 18 . However, less is known about the relation of ADRB1 variants to the pathology and pharmacogenetics of ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)

Magvanjav

McDonough

Gong

et al. 2017

Stroke

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Background and Purpose Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and β-blocker response outcomes. Herein we examined associations of these polymorphisms with Major Adverse Cardiovascular Events (MACE), with and without stratification by β-blocker treatment in patients with a history of stroke. Methods 926 participants of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial’s genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41,475 individuals of European and African ancestry in the NINDS Stroke Genetics Network (SiGN). Results MACE was higher in carriers of the Gly49 allele than those with the Ser49Ser genotype (10.5% vs. 5.4%, log-rank p=0.005). Gly49 carrier status was associated with MACE (HR 1.62; 95% CI 1.00–2.68) and ischemic stroke (HR 1.81; 95% CI 1.01–3.23) in SPS3 and with small artery ischemic stroke (OR 1.14; 95% CI 1.03–1.26) in SiGN. In SPS3, β-blocker-treated Gly49 carriers had increased MACE versus non-β-blocker-treated individuals and non-carriers (HR 2.03; 95% CI 1.20–3.45). No associations were observed with the Arg389Gly polymorphism. Conclusion Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among β-blocker-treated individuals. Further research is needed to define β-blocker benefit among ischemic stroke patients by ADRB1 genotype. Clinical Trial Registration-URL http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

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Adrenergic Receptor Polymorphisms Associated with Resting Heart Rate: The HyperGEN Study

Cited by 28 publications

References 21 publications

Human Heart Rate

Human Heart Rate

AGT M235T Genotype/Anxiety Interaction and Gender in the HyperGEN Study

Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)

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