Key result
Homozygous carriers of the ADRA2A rs553668 variant exhibited a 2.2-fold greater decrease in systolic blood pressure AUC after dexmedetomidine infusion compared to wild-type carriers (P=0.006).
Why the study?
Are ADRA2A genetic variants associated with the blood pressure response to dexmedetomidine in healthy subjects?
RCT (n=73)
Single-blind
Are ADRA2A genetic variants associated with the blood pressure response to dexmedetomidine in healthy subjects?
Effect estimate: 2.2-fold greater decrease
p-value: p=0.006
Common ADRA2A genetic variants significantly influence the hypotensive response to the alpha-2 agonist dexmedetomidine in healthy subjects.
May inform genotype-guided dexmedetomidine dosing; hypothesis-generating and requires validation in patients.
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(2)-AR-agonist 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 AUC(SBP) 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 AUC(SBP) (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.
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Kurnik et al. (2011) conducted an RCT in Healthy subjects (n=73). Dexmedetomidine vs. Placebo was evaluated on 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) (2.2-fold greater decrease, p=0.006). Homozygous carriers of the ADRA2A rs553668 variant exhibited a 2.2-fold greater decrease in systolic blood pressure AUC after dexmedetomidine infusion compared to wild-type carriers (P=0.006).
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