Genetic variations in the α_2A-Adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine

Background: α_2A-Adrenoceptors (α_2A-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2A affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2A variants are also associated with cardiovascular responses to the selective α_2A-ARagonist dexmedetomidine. Methods and Results: Seventy-three healthy subjects participated in a placebo-controlled, single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 μg/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (δAUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and δAUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased α_2A-AR expression, had a 2.2-fold greater decrease in AUCSBP after dexmedetomidine (adjusted P=0.006); similarly, the maximum decrease in SBP was 24.7±8.1 mm Hg compared with 13.6±5.9 mm Hg in carriers of the wild-type allele (P=0.007). Carriers of haplotype 3, previously associated with reduced α_2A-AR expression, had a 44% smaller decrease in AUCSBP (P=0.013). Haplotype information significantly improved the model predicting the decrease in SBP (P=0.001). There were similar but nonsignificant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses. Conclusions: Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro.