2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Circulation (Impact Factor: 14.43). 05/2006; 113(15):1842-8. DOI: 10.1161/CIRCULATIONAHA.105.582833
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "Recent candidate gene association studies for SCA have yielded conflicting results for common variants in the ß2 adrenergic receptor gene[8,9], possibly due to different SCA phenotype definitions - community-based SCA cases as compared to SCA cases due to documented VT/VF in the setting of CAD[10]. Other recent candidate gene studies have yielded associations with SCA for single nucleotide polymorphisms (SNPs) in angiotensin-converting enzyme pathway genes and the transforming growth factor ß-receptor 2 gene, but have yet to be validated[11,12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study. Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls. Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 × 10(-7)), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 10(-8); Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 × 10(-4); OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 × 10(-2), OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10(-3), OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 10(-3), OR = 1.13, 95% CI:1.042, 1.215). We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.
    Full-text · Article · Jun 2011 · BMC Cardiovascular Disorders
    • "Effect of allelic variations affecting sympathetic tone on sudden death has been demonstrated in two studies. In both the Cardiovascular Health Study as well as the Cardiac Arrest Blood Study, the Q27E variant of the beta 2 receptor was associated with more sudden deaths than the other common variant, the G16R receptor1415. The DD variant of the ADRA2B gene, which mediates coronary vasoconstriction, was associated with a higher risk of sudden death in the Helsinki Sudden Death Study16. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent advances in molecular biology have advanced our understanding of the genetic substrate predisposing to sudden death, especially in monogenic disorders. Numerous ion channels along with membrane structural proteins have been extensively investigated for their role in the genesis of serious ventricular tachyarrhythmias. The complex interplay of various biological pathways culminating in the more prevalent form of sudden death due to coronary artery disease however still remains to be unraveled. The concept of multi-factorial causation of arrhythmias where a second clinical or environmental factor is necessary for expression of an underlying genetic susceptibility to ventricular arrhythmias is a serious possibility. This article briefly outlines the current understanding about the role of genetics in sudden cardiac death.
    No preview · Article · Nov 2010 · The Indian Journal of Medical Research
  • Source
    • "Other investigators explored associations of β 2 -AR variants on the risk of sudden cardiac death in an older adult cohort, on mortality in individuals following an acute coronary syndrome, and on the risk of death and heart transplantation in patients with heart failure.[32] [33] [34] Elevated cardiovascular risk was associated with the Gln27Gln and Arg16Arg genotypes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin resistance is prevalent in heart failure (HF) patients, and beta2 adrenergic receptors (beta2-AR) are involved in glucose homeostasis. We hypothesized that beta2-AR Gln27Glu and Arg16Gly polymorphisms affect insulin resistance in HF patients, and we explored if effects of beta2-AR polymorphisms on glucose handling are modified by choice of beta blocker. We studied 30 nondiabetic adults with HF and a history of systolic dysfunction; 15 were receiving metoprolol succinate, and 15 were receiving carvedilol. We measured fasting glucose, insulin, and insulin resistance, and we determined beta2-AR genotypes at codons 27 and 16. The cohort was insulin resistant with a mean HOMA-IR score of 3.4 (95% CI, 2.3 to 4.5; normal value, 1.0). Patients with the Glu27Glu genotype exhibited higher insulin and HOMA-IR compared to individuals carrying a Gln allele (P = 0.019). Patients taking carvedilol demonstrated lower insulin resistance if also carrying a wild-type allele at codon 27 (fasting insulin, 9.8 +/- 10.5 versus 20.5 +/- 2.1 for variant, P = 0.072; HOMA-IR, 2.4 +/- 2.7 versus 5.1 +/- 0.6, P = 0.074); those on metoprolol succinate had high insulin resistance irrespective of genotype. The beta2-AR Glu27Glu genotype may be associated with higher insulin concentrations and insulin resistance in patients with HF. Future studies are needed to confirm whether treatment with carvedilol may be associated with decreased insulin and insulin resistance in beta2-AR codon 27 Gln carriers.
    Full-text · Article · Dec 2008 · Journal of cardiovascular pharmacology
Show more