A genetic polymorphism of the α₂-adrenergic receptor increases autonomic responses to stress

Abstract

We hypothesized that individual differences in autonomic responses to psychological, physiological, or environmental stresses are inherited, and exaggerated autonomic responsiveness may represent an intermediate phenotype that can contribute to the development of essential hypertension in humans over time. alpha(2)-Adrenergic receptors (alpha(2)-ARs), encoded by a gene on chromosome 10, are found in the central nervous system and also mediate release of norepinephrine from the presynaptic nerve terminals of the peripheral sympathetic nervous system and the exocytosis of epinephrine from the adrenal medulla. We postulated that, because this receptor mediates central and peripheral autonomic responsiveness to stress, genetic mutations in the gene encoding this receptor may explain contrasting activity of the autonomic nervous system among individuals. The restriction enzyme Dra I identifies a polymorphic site in the 3'-transcribed, but not translated, portion of the gene encoding the chromosome 10 alpha(2)-AR. Southern blotting of genomic DNA with a cDNA probe after restriction enzyme digestion results in fragments that are either 6.7 kb or 6.3 kb in size. Transfection studies of these two genotypes resulted in contrasting expression of a reporter gene, and it is suggested from these findings that this is a functional polymorphism. In a study of 194 healthy subjects, we measured autonomic responses to provocative motion, a fall in blood pressure induced by decreasing venous return and cardiac output, or exercise. Specifically, we measured reactions to 1) Coriolis stress, a strong stimulus that induces motion sickness in man; 2) heart rate responses to the fall in blood pressure induced by the application of graded lower body negative pressure; and 3) exercise-induced sweat secretion. In all of these paradigms of stress, subjective and objective evidence of increased autonomic responsiveness was found in those individuals harboring the 6.3-kb allele. Specifically, volunteers with the 6.3-kb allele had greater signs and symptoms of motion sickness mediated by the autonomic nervous system after off-axis rotation at increasing velocity (number of head movements a subject could complete during rotation before emesis +/- SE: 295 +/- 18 vs. 365 +/- 11; P = 0.001). They also had greater increases in heart rate in responses to the lower body negative pressure-induced fall in blood pressure (increase in heart rate +/- SE: 3.0 +/- 0.4 vs. 1.8 +/- 0.3; P = 0.012), and the 6.3-kb group had higher sweat sodium concentrations during exercise (mean sweat sodium concentration in meq/l over 30 min of exercise +/- SE: 43.2 +/- 7.1 vs. 27.6 +/- 3.4; P < 0.05). This single-nucleotide polymorphism may contribute to contrasting individual differences in autonomic responsiveness among healthy individuals.

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.…”

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.…”

“…Except for the drastic high-expression phenotype observed with haplotype 10, the maximal difference in mRNA expression between the other haplotypes was Ϸ2-fold. Of note, the DraI RFLP has been studied in isolation by using a vector with the reporter gene chloramphenicol acetyltransferase placed 5Ј to a portion of the ␣ 2A AR 3Ј UTR (13). (Transcription was driven by elements within the vector pcDNA3.)…”

“…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.…”

Do Allelic Variants in α 2A and α 2C Adrenergic Receptors Predispose to Hypertension in Blacks?

“…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).…”