An insertion/deletion polymorphism in the α2b-adrenergic receptor gene is a novel genetic risk factor for acute coronary events

Snapir, Amir; Heinonen, Petri; Tuomainen, Tomi‐Pekka; Alhopuro, T. Pia; Karvonen, Matti K.; Lakka, Timo A.; Nyyssönen, Kristiina; Salonen, Tuula; Kauhanen, Jussi; Valkonen, Tuomo; Pesonen, T. Ullamari; Koulu, Markku; Scheinin, Mika; Salonen, Jukka T.

doi:10.1016/s0735-1097(01)01201-3

Cited by 104 publications

(102 citation statements)

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“…19 Because our study was designed to assess sympathetic activation through ␣ 2 -AR blockade, individuals with cardiac morbidity, such as myocardial infarction, were excluded. Consistent with the results of Snapir et al, 15,16 our initial analysis of the 173 individuals who underwent testing with yohimbine revealed a decrease in Del/Del individuals aged 40 and older, suggesting a selection "bias" caused by the lack of healthy older individuals with that genotype, because individuals with Del/Del might have experienced premature mortality or been excluded because of previous cardiovascular disease. However, subsequent analysis in 2 larger groups of subjects, including those drawn from a large populationbased cohort with extreme values for BP, failed to confirm our initial conclusions from the smaller-sized population.…”

Section: Discussionsupporting

confidence: 87%

“…Evidence has been reported in a Finnish population that the deletion polymorphism, particularly Del/Del homozygosity, increases the risk for acute coronary events and sudden cardiac death. 15,16 Other data have provided possible mechanistic explanations for the impact of the Del/Del genotype on cardiovascular risk through increased vasoconstriction of the coronary vasculature, 17 endothelial dysfunction as defined by decreased flow Etzel et al Genetic Variation of the ␣ 2B -Adrenergic Receptormediated dilatation, 18 and association with obesity. 19 Because our study was designed to assess sympathetic activation through ␣ 2 -AR blockade, individuals with cardiac morbidity, such as myocardial infarction, were excluded.…”

Section: Discussionmentioning

confidence: 99%

“…13 Homozygosity for a 9-bp in-frame deletion (Del) of 3 glutamic acid residues (Glu 301 to Glu 303 ) in the third intracellular loop of the ␣ 2B receptor, which leads to decreased agonist-stimulated desensitization, 14 has been associated with increased risk of myocardial infarction and sudden cardiac death, 15,16 vasoconstriction of the coronary vasculature, 17 endothelial dysfunction (as defined by decreased flow-mediated dilation) 18 and obesity. 19 Although some studies have found no association between this genotype and hypertension, 15,20 individuals homozygous for the deletion were reported to have increased risk for early-onset hypertension. 21 Akin to the ␣ 2B -AR, the ␣ 2C -AR has a 12-bp deletion variant in its third intracellular loop, which leads to decreased coupling of the receptor to G␣ i 22 ; blacks homozygous for the deletion allele are at increased risk for developing congestive heart failure.…”

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confidence: 99%

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confidence: 99%

“…12 Common genetic variants in the ␣ 2 -ARs have been associated with cardiovascular pathology. 13 Homozygosity for a 9-bp in-frame deletion (Del) of 3 glutamic acid residues (Glu 301 to Glu 303 ) in the third intracellular loop of the ␣ 2B receptor, which leads to decreased agonist-stimulated desensitization, 14 has been associated with increased risk of myocardial infarction and sudden cardiac death, 15,16 vasoconstriction of the coronary vasculature, 17 endothelial dysfunction (as defined by decreased flow-mediated dilation) 18 and obesity. 19 Although some studies have found no association between this genotype and hypertension, 15,20 individuals homozygous for the deletion were reported to have increased risk for early-onset hypertension.…”

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confidence: 99%

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Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Etzel

Rana²,

Wen³

et al. 2005

Hypertension

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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...

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Section: Discussionsupporting

confidence: 87%