Do Allelic Variants in α _2A and α _2C Adrenergic Receptors Predispose to Hypertension in Blacks?

Abstract

Abstract-Sequence variations in the human ␣ 2 adrenergic receptor genes (ADRA2A and ADRA2C) have been implicated as a cause of hypertension in blacks. Although certain alleles are selectively enriched in blacks, their association with hypertension is based on small convenience samples and has not been evaluated in larger populations. From a stratified random population sample of 3398 individuals (52% blacks), we obtained DNA samples together with an in-home health interview, 10 in-home measurements of blood pressure, and cardiac MRI. We tested for associations among hypertension, untreated blood pressure, and parameters of hypertensive heart disease with 2 alleles, a DraI restriction fragment length polymorphism in the ADRA2A gene and a deletion of residues 322 to 325 in the ADRA2C gene. Although both alleles were selectively enriched in this black population, we found no association of either allele with hypertension, untreated blood pressure, or any of the cardiac function parameters. In a logistic model that controlled for age, body mass index, diabetes, and smoking, the adjusted odds ratio (OR) for hypertension was 1.0 (95% CI, 0.8 to 1.2), and 1.0 (95% CI, 0.9 to 1.2) for ADRA2A and ADRA2C variant alleles. In subjects not receiving prescription blood pressure medication, neither of these alleles, alone or in combination, was predictive of blood pressure, heart rate, left ventricular mass, cardiac output, systemic vascular resistance, or aortic compliance. Both the DraI restriction fragment length polymorphism in ADRA2A and the ADRA2C (Del 322 to 325) can be excluded as major candidate alleles for hypertension in blacks. Key Words: hypertension, genetics Ⅲ receptors, adrenergic alpha Ⅲ polymorphisms Ⅲ sympathetic nervous system I n blacks, hypertension is more prevalent, more severe, and causes more disability and death than in other ethnic groups in the United States. 1-6 Despite numerous hypotheses, a genetic underpinning to this excessive hypertension has been difficult to define. 7 Two allelic variants in the human ␣ 2 adrenergic receptor (AR) genes are selectively enriched in blacks and seem to impair receptor function. 8,9 In mice, ␣ 2A and ␣ 2C AR subtypes decrease sympathetic drive to the heart and peripheral circulation, 10 such that loss-of-function mutations might predispose to hypertension.The first allele, a DraI restriction fragment length polymorphism (RFLP) in the 3Ј-untranslated region of the ADRA2A gene, is 50% more common in blacks than whites. 11 The variant allele produces a less stable transcript, which could increase sympathetic drive and blood pressure (BP). 8 This allele has been associated with increased hypertension prevalence 11 and increased cardiovascular reactivity in normotensive young adults. 8,12 The second variant allele, which is 10-fold more common in blacks than non-blacks, encodes a 4-amino acid deletion in the human ␣ 2C AR (Del 322 to 325). 9 In heterologous systems, the ␣ 2c Del322-325 receptor displays depressed agonist-induced coupling to inhibitory G proteins, 9 w...

Ethnic and Genetic Determinants of Cardiovascular Response to the Selective α 2 -Adrenoceptor Agonist Dexmedetomidine

“…5 However, larger studies found no associations between the ADRA2C deletion and markers of elevated resting sympathetic tone, blood pressure, or heart rate. 10,22 Variable results regarding the association between the ADRA2C deletion variant and cardiac function 14,23 suggest that the functional effects of the deletion variant may be most apparent in circumstances of substantially elevated sympathetic tone (eg, after yohimbine administration or in advanced congestive heart failure), and only in subjects who are homozygous for the deletion. 10,24 Another approach to examine the functional consequences of the ADRA2C deletion is to administer an ␣ 2 -AR agonist.…”

Environmental, societal, and genetic contributions to the epidemic of hypertension in African Americans

“…Sequence variations in the human α -2 adrenoreceptor genes have been implicated as a cause of hypertension in African Americans. A study of adrenoreceptor genes (ADRA2A and ADRA2C) from the Dallas Heart Study did not fi nd an association with hypertension in African Americans despite evidence of selective enrichment of these alleles in African Americans [ 42 ]. Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans.…”

Genetic Variations of α2-Adrenergic Receptors Illuminate the Diversity of Receptor Functions

“…These two pieces of evidence illustrate the variability in conclusions commonly seen among different genetic association studies. The largest association study for a 2 ARs and hypertension carried out to date by Li, Canham, Vongpatanasin, Leonard, Auchus, and Victor (2006) revealed negative results for both the a 2A AR DraI RFLP and a 2C AR Del322-325 variant and associations with hypertension and parameters of hypertensive heart disease. Other a 2A AR polymorphisms have been studied in the context of hypertension, with no association found between a novel Bsu361 RFLP and hypertension in a Japanese population (Umemura et al, 1994).…”