Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Abstract

Abstract-Exaggerated response to ␣ 2 -adrenergic receptor (␣ 2 -AR) blockade by yohimbine in normotensive subjects is an intermediate phenotype that predicts increased risk for development of hypertension. Here, we assessed the 3 ␣ 2 -AR loci (␣ 2A, ␣ 2B, ␣ 2C ) as candidate genes for their influence on baseline and yohimbine-mediated increase in mean arterial pressure. Because initial results with 173 individuals implicated a possible association of yohimbine response with genetic variation at a site in the ␣ 2B -AR gene, but not at sites in the other 2 ␣ 2 -AR, we sequenced the ␣ 2B -AR gene (4.4 kb, including 1.2 kb upstream and 1.9 kb distal to the coding sequence) in those subjects and an additional 81 individuals to search for other ␣ 2B -AR variants. We identified 25 polymorphisms, of which 14 are previously unreported, and 2 major haplotypes that differ by the presence/absence of a 9-bp in-frame deletion that encodes Glu 301 to Glu 303 . Frequency differences in haplotypes were observed between blacks and whites but did not predict response to yohimbine. Genotyping of 2 additional white cohorts, including 1269 individuals with extremes in blood pressure selected from Ͼ50 000 subjects, also failed to reveal an association of the 2 major ␣ 2B -AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in ␣ 2 -AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension. he sympathetic nervous system regulates cardiovascular physiology primarily by the release of catecholamines and activation of adrenergic receptors (AR). Multiple subtypes of ␣ 1 -, ␣ 2 -, and ␤-AR regulate cardiovascular cells and contribute to the pathophysiology of cardiovascular disease. 1 For example, heritable differences in ␣ 2 -AR subtypes have been implicated in human 2 and rodent 3 hypertension. The 3 ␣ 2 -AR subtypes in the human genome, ␣ 2A , ␣ 2B , and ␣ 2C , are located on separate chromosomes, expressed in different locations, and regulate different functional responses. 1,4 ␣ 2 -AR agonists have an antihypertensive effect that is primarily attributed to stimulation of central presynaptic receptors and a decrease in sympathetic activity 5 as a consequence predominantly of central ␣ 2A -AR. 6,7 ␣ 2C -AR also contributes to this response, especially at low levels of stimulation of nerve activity. 6 Although central inhibition of sympathetic outflow not does involve ␣ 2B -AR, the receptor may have a role in blood pressure (BP) through peripheral effects. Mice with a knockout of 1 copy of the ␣ 2B -AR are resistant to the development of salt-induced hypertension. 8 Moreover, the latter form of hypertension is partially dependent on neural mechanisms and expression of ␣ 2B -AR, because it can be treated by injection of antisense ␣ 2B receptor DNA into the cerebrospinal fluid. 9 It is unclear whether this salt-induced hypertensive effect is mediated by central ␣ 2B -AR or receptors in the periphery. Acti...

Association of <i>CSK, MTHFR, ACE, ADRA2B, TCF7L2</i> gene polymorphisms with dyslipidemia among indigenous and non-indigenous people of Khanty-Mansy Autonomous Okrug – Yugra

“…Установлена роль гена ADRA2B, кодирующего трансмембранный белок из семейства рецепторов, связанных с G-белком. Данный белок регулирует высвобождение нейротрансмиттеров из симпатических нервов и из адренергических нейронов в ЦНС, что приводит к подавлению липолиза в липоцитах, угнетению секреции инсулина, стимуляции агрегации тромбоцитов и сужению сосудов [3,16]. Интерес к гену TCF7L2 и его изменчивости связан с повышенным риском развития сахарного диабета 2 типа.…”