Genetic polymorphism of the α2-adrenergic receptor is associated with increased platelet aggregation, baroreceptor sensitivity, and salt excretion in normotensive humans

Abstract

It is likely that a number of independent heritable traits, each encoded by a singular gene, contribute to pathologic elevations in blood pressure in humans. Genetic polymorphisms of individual genes may result in intermediate phenotypes which, by themselves, do not raise blood pressure, but, coupled with environmental or epistatic forces, contribute to the prevalence of human hypertension. The gene for the alpha 2-adrenergic receptor encoded by chromosome 10 (C10 A2AR) is polymorphic, and Southern blotting with a cDNA probe following restriction enzyme digest of this gene results in fragments of either 6.3 kb or 6.7 kb in size. We reported an association between homozygosity for the 6.3 kb allele and hypertension in blacks. Blacks with hypertension also have an increased risk for thrombotic stroke, increased baroreceptor sensitivity, and decreased sodium excretion. We noted that the C10 A2AR, which modulates norepinephrine release in blood-pressure-regulating regions of the brain, is also expressed on platelets and in the kidney. We postulated that functional changes associated with the C10 A2AR gene polymorphism could be responsible for increased baroreceptor sensitivity, epinephrine-mediated platelet aggregation, and decreased sodium excretion in some individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-adrenoceptor gene variants and autonomic nervous system function in a young healthy Japanese population

“…Conversely, the 6.3-kb allele of the DraI RFLP and -1291G allele of ADRA2A were more common in Asians (Small et al 2006), including a Japanese population ( Table 1). The DraI RFLP has been reported to be associated with hypertension and increased autonomic responsiveness to some stressful conditions (Finley et al 2004;Freeman et al 1995;Lockette et al 1995). In the present study, we found that heterozygous carriers of the 6.3-kb allele showed a lower HF and LF component power of HRV compared with 6.7-kb homozygous carriers; however, significant differences were not observed in comparison with 6.3-kb homozygous carriers.…”

“…However, the 251Lys allele frequency was found to be relatively rare, e.g., 0.4% in Caucasian and 5% in African Americans (Small et al 2003). DraI RFLP of 6.3-and 6.7-kb alleles has been found in the 3¢ UTR of ADRA2A and has been reported to be associated with essential hypertension , increased cardiovascular reactivity, body fat distribution (Oppert et al 1995), platelet aggregation (Freeman et al 1995), and glucose metabolism (Ukkola et al 2000). The C-1291G polymorphism is located in the promoter region of ADRA2A.…”

Mechanism of Epinephrine-Induced Platelet Aggregation

“…2,6 In a population-based study of urban Detroit blacks, we reported a strong association between homozygosity for the 6.3-kb allele of the C10 A2AR gene and hypertension. 2 Subsequently, we noted that normotensive individuals carrying at least one allele of the 6.3-kb C10 A2AR had increased epinephrine-mediated platelet aggregation compared with individuals homozygous for the 6.7-kb allele, and transfection studies with these genotypes demonstrated that this polymorphism was functional.…”

Complex haplotypes derived from noncoding polymorphisms of the intronless α 2A -adrenergic gene diversify receptor expression

“…However, another study in European Caucasians found no association between this RFLP and hypertension or a family history of hypertension (37). The DraI RFLP has been associated with modest increases in autonomic responses to maneuvers that lower blood pressure, exercise-induced sweat secretion, provocative motion, and platelet aggregation (13,14). As can be seen from Table 3, the A at SNP position 1780, which represents the minor allele of the DraI RFLP, is present in six different haplotypes with frequencies ranging from 0.0125 to 0.225.…”

“…The critical roles of ␣ 2A ARs in these physiologic processes has prompted association and family studies of receptor genetic variability to identify potential risk factors or disease modifiers and pharmacogenomic studies to identify potential treatment-response loci for multiple central nervous system, cardiovascular, and metabolic diseases (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). These studies were performed with single restriction fragment-length polymorphisms (RFLPs) of the ␣ 2A AR gene, such as a DraI RFLP, and generally have shown only weak or no associations or a lack of reproducibility.…”