A common variant in the β2-adrenergic receptor and risk of sudden cardiac death

BACKGROUND Homozygosity for a common nonsynonymous single nucleotide polymorphism (Gln27Glu) in the beta(2)-adrenergic receptor gene (ADRB2) has been inconsistently associated with sudden cardiac death (SCD) in individual studies of small sample size. OBJECTIVE The purpose of this study was to examine the association between the Gln27Glu polymorphism and SCD in a large combined sample of SCD cases. METHODS Nested case-control analysis was performed for individuals of Caucasian ancestry enrolled in six prospective cohort studies. Genotypes for the Gln27Glu variant were determined for 492 cases of SCD and 1,388 controls matched for age, sex, cohort, follow-up time, and history of cardiovascular disease (CVD) and at the time of the blood draw. Individual studies were combined with conditional logistic regression with fixed effects meta-analysis assuming a recessive model. RESULTS Homozygosity for the Gln27 allele conferred a nonsignificant elevation of the age-adjusted odds ratio (OR 1.22, 95% confidence interval [CI] 0.98-1.53, P = .08) for SCD, which became marginally significant after controlling for multiple cardiac risk factors (OR 1.30, 95% CI 1.01-1.67, P = .046). In secondary analyses using controls additionally matched for the development of nonfatal CVD after the blood draw, results were attenuated (OR 1.19, 95% CI 0.92-1.52, P = .19). When the results of the primary analysis were combined in meta-analysis with published reports, a significant association between ADRB2 genotype and SCD emerged (OR 1.35, 95% CI 1.15-1.60, P = .0003). CONCLUSION These data from a large prospective case-control series, when combined with published studies, provide further evidence for an association between ADRB2 genotype and SCD. The mechanism is unknown but appears to be partly mediated by development of CVD.