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Genetic variations in the ?(2A)-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine.

ABSTRACT: ?(2A)-Adrenoceptors (?(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 ?(2)-AR-agonist dexmedetomidine.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 ?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 (?AUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and ?AUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased ?(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 ?(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.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.

SUBMITTER: Kurnik D

PROVIDER: S-EPMC3080459 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Genetic variations in the α(2A)-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine.

Kurnik Daniel D Muszkat Mordechai M Li Chun C Sofowora Gbenga G GG Friedman Eitan A EA Scheinin Mika M Wood Alastair J J AJ Stein C Michael CM

Circulation. Cardiovascular genetics 20110215 2

<h4>Background</h4>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.<h4>Methods and results</h4>Seventy-three healthy subjects participated in a placebo-controlled, single-blind study. Afte ...[more]

PMID: 21325151

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Project description:Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaC? subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure.We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ? 0.01 in one cohort and replication by P ? 0.05 in the other cohort considered significant.In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.

Dataset Information

Genetic variations in the ?(2A)-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine.

Publications

Genetic variations in the α(2A)-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine.

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