Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death.
ABSTRACT Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.
In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.
Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
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ABSTRACT: Abnormal calcium handling plays a crucial role in arrhythmias, sudden cardiac arrest (SCA), and congestive heart failure (CHF). Calsequestrin 2 (CASQ2) mutations affect calcium release and initiate malignant ventricular arrhythmias (VA) and SCA syndromes. Common single nucleotide polymorphisms (SNPs) in CASQ2 may be associated with SCA in patients with coronary artery disease (CAD). We examined the association of common CASQ2 SNPs with the risk of SCA in patients with CAD. CASQ2 SNPs (n=14) were genotyped and analyzed in a case-control study comparing 114 patients with CAD and SCA due to ventricular arrhythmias (VA) to 311 CAD controls without VA or SCA. Multivariate logistic regression adjusting for age and CHF status identified an association between rs7521023 with SCA (odds ratio [OR] 2.72, 95% confidence interval (CI): 1.44-5.13, p=0.002). The substantial impact of CHF on SCA in the model (OR 26.6, 95% CI: 13.40-52.70, p<0.001) led us to further examine the relationship between CHF, SCA, and CASQ2 SNPs. We identified 2 CASQ2 variants (rs7521023 [OR 0.4, 95% CI 0.25-0.76, p=0.003] and rs6684209 [OR 19.8, 95% CI 3.63-108.2 , p<0.001]) associated with CHF after adjusting for SCA, age, gender, and hypertension. We observed association between a CASQ2 polymorphism and SCA due to VA in patients with CAD adjusting for CHF, and independent associations between CASQ2 SNPs and CHF adjusting for SCA. Further investigation in independent cohorts is needed to confirm these findings.Heart rhythm: the official journal of the Heart Rhythm Society 01/2014; · 4.56 Impact Factor
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ABSTRACT: β2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective β-AR blockers have greater benefits on survival than selective β1-AR blockers in chronic HF patients, indicating that β2-AR activation contributes to SCD in HF. This study investigated the role of β2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective β2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective β2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that β2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways.Scientific reports. 01/2015; 5:7681.
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ABSTRACT: The human genome encodes nine different adrenoceptor genes. These are grouped into three families, namely, the α1-, α2-, and β-adrenoceptors, with three family members each. Adrenoceptors are expressed by most cell types of the human body and are primary targets of the catecholamines epinephrine and norepinephrine that are released from the sympathetic nervous system during its activation. Upon catecholamine binding, adrenoceptors change conformation, couple to and activate G proteins, and thereby initiate various intracellular signaling cascades. As the primary receivers and transducers of sympathetic activation, adrenoceptors have a central role in human physiology and disease and are important targets for widely used drugs. All nine adrenoceptor subtypes display substantial genetic variation, both in their coding sequence as well as in adjacent regions. Despite the fact that some of the adrenoceptor variants range among the most frequently studied genetic variants assessed in pharmacogenetics to date, their functional relevance remains ill defined in many cases. A substantial fraction of the associations reported from early candidate gene approaches have not subsequently been confirmed in different cohorts or in genome-wide association studies, which have increasingly been conducted in recent years. This review aims to provide a comprehensive overview of all adrenoceptor variants that have reproducibly been detected in the larger genome sequencing efforts. We evaluate these variants with respect to the modulation of receptor function and expression and discuss their role in physiology and disease.Pharmacological reviews 07/2014; 66(3):598-637. · 18.55 Impact Factor