Genetic Variations in the alpha(2A)-Adrenoreceptor Are Associated With Blood Pressure Response to the Agonist Dexmedetomidine

作者：Kurnik Daniel; Muszkat Mordechai; Li Chun; Sofowora Gbenga G; Friedman Eitan A; Scheinin Mika; Wood Alastair J J; Stein C Michael^*

来源：Circulation-Cardiovascular Genetics, 2011, 4(2): 179-U245.

DOI：10.1161/CIRCGENETICS.110.957662

• receptors, adrenergic, alpha
• genetic polymorphism
• pharmacogenetics
• receptor
• variability in drug response

Background-alpha(2A)-Adrenoceptors (alpha(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 alpha(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 mu g/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 (Delta AUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and Delta AUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased alpha(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 alpha(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. (Circ Cardiovasc Genet. 2011;4:179-187.)

• 出版日期2011-4