Identification of a polymorphic glutamic acid stretch in the α2b-adrenergic receptor and lack of linkage with essential hypertension

Baldwin, Clinton T.; Schwartz, Faina; Baima, Jader; Burzstyn, Michael; DeStefano, Anita L.; Gavras, Irène; Handy, Diane E.; Joost, Oscar; Martel, Timothy; Manolis, Athanasios; Nicolaou, Michael; Bresnahan, Margaret; Farrer, Lindsay A.; Gavras, Haralambos

doi:10.1016/s0895-7061(99)00070-9

Cited by 39 publications

(36 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…With respect to hypertension, our data in the large cohorts are consistent with an earlier study with a smaller sample 20 but contrast with those of Von Wowern et al (2004), 21 who showed an increased risk (ORϭ2.01) for early-onset (younger than 50 years old) hypertension in Swedish ␣ 2B -AR Del/Del homozygotes, an effect that lost significance in an all-age population. Even when we stratified our data and compared younger versus older subjects (using age 40, as reported, or when we used age 50 as a cutoff, data not shown), we failed to find evidence to support the conclusions of Von Wowern et al (2004), perhaps because of differences between our white population and their more ethnically homogenous Swedish population.…”

Section: Discussionsupporting

confidence: 84%

“…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 a Swedish population of 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.…”

mentioning

confidence: 97%

See 1 more Smart Citation

Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Etzel

Rana²,

Wen³

et al. 2005

Hypertension

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 97%

Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Etzel

Rana²,

Wen³

et al. 2005

Hypertension

View full text Add to dashboard Cite

show abstract

“…8,19 However, in one of these studies, 19 hypertension was a secondary phenotype making the results exposed to greater uncertainty as compared with a study primarily designed for studying hypertension. In addition, only 206 patients with hypertension were included and, in contrast to our study, age at onset, diabetic state, and albuminuria were not taken into account in the analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Absence of the D is referred to as the insertion (I) variant. 8,9 The third intracellular loop of the ␣ 2B -adrenergic receptor, which harbors the I/D polymorphism, has been shown to be instrumental for the function of the receptor. 10 The functional importance of the I/D polymorphism has been shown by in vitro studies revealing an impaired agonist-induced desensitization of the D-variant of the receptor.…”

mentioning

confidence: 99%

Functional Variant in the α _2B Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension

et al. 2004

View full text Add to dashboard Cite

Abstract-In a genome-wide scan in Scandinavians, we found suggestive linkage between early-onset primary hypertension and a region on chromosome 2. The ␣ 2B -adrenoceptor gene, a candidate gene within this region, harbors a functional insertion/deletion (I/D) polymorphism of three glutamate residues. The aim of this study was to investigate if the DD genotype is associated with hypertension in Swedes. We performed an association study between the I/D polymorphism of the ␣ 2B -adrenoceptor and hypertension in the Skaraborg population. The material consists of all known patients with primary hypertension in Skara (nϭ772 nondiabetic subjects; nϭ171 normoalbuminuric type 2 diabetic subjects) and 817 population control subjects. We first compared genotype frequencies between patients with early-onset hypertension (aged 50 years or younger at onset) and subjects with normotension (blood pressure Ͻ120/80 mm Hg). Thereafter, the polymorphism was tested for association with hypertension at the population level. When comparing patients with early-onset hypertension and normotensive subjects, the DD versus II genotype was associated with early-onset hypertension when diabetic subjects were excluded from the analysis (ORϭ2.0; 95% CIϭ1.2 to 3.5) or when they were not excluded (ORϭ1.8; 95% CIϭ1.0 to 3.1). At the population level, the DD versus II genotype was weakly associated with nondiabetic hypertension (ORϭ1.4; 95% CIϭ1.0 to 1.8). Our data suggest that carriers of the DD versus II genotype of the ␣ 2B -adrenoceptor are at increased risk for hypertension. The genotypic effect is most evident when comparing groups corresponding to the upper and lower tails of the blood pressure distribution in the population; however, in nondiabetic hypertensive subjects it is weakly detectable even at the population level. Key Words: receptors Ⅲ adrenergic Ⅲ genetics Ⅲ hypertension H uman primary hypertension is likely to be of a complex nature, arising from environmental and genetic factors. A positive family history of hypertension strongly predicts early-onset hypertension, but the predictive value gradually decreases with increasing age at onset of the disease. 1 This suggests that hypertension susceptibility gene variants are more common in patients with early-onset primary hypertension (EOHT) than in patients with late-onset hypertension.To clarify the genetics behind blood pressure variation and the development of primary hypertension, a wide variety of techniques have been developed. Of these, the genome-wide scan method is the only one that can identify regions of the genome that are linked to variation in blood pressure and to primary hypertension independently of available physiological knowledge of blood pressure regulation. We recently published a genome-wide scan for EOHT in Scandinavian families and found suggestive evidence of linkage on chromosome 2 with a 1-LOD decrease interval stretching between Ϸ109 to 121 cM. 2 Interestingly, this locus overlaps with linkage results of several other genome-wide scans for hypertension ...

show abstract

“…[1][2][3][4] The functional significance of the 12Glu9 polymorphism of the a 2B -AR gene investigated in vitro cell culture model indicated that the Glu9 variant was associated with impaired receptor desensitization properties under prolonged agonist activation as compared with the Glu12 variant. 5 Studies in obese humans demonstrated that the homozygote short form of a 2B alleles (Glu 9 /Glu 9 ) were associated with slower heart rate (HR).…”

Section: Introductionmentioning

confidence: 99%

α2B-Adrenergic receptor deletion polymorphism and cardiac autonomic nervous system responses to exercise in obese women

et al. 2005

View full text Add to dashboard Cite

Objective: To investigate the association of short form (Glu 9 /Glu 9 ) of the 12Glu9 deletion polymorphism of the a 2B -adrenergic receptor (a 2B -AR) gene polymorphism with the cardiac autonomic responsiveness during sustained isometric handgrip exercise. Design: Cross-sectional clinical study. Subjects: In all, 97 normotensive obese women (body mass index (BMI) ¼ 33.2 kg/m 2 ). Of these, 78 (80.41%) were genotyped as Glu 12 /Glu 12 , 13 (13.40%) as Glu 12 /Glu 9 and six (6.19%) as Glu 9 /Glu 9 form. Measurements: The sympathovagal balance was assessed by means of power spectral analysis of heart rate variability at rest and during sustained isometric handgrip exercise at 30% of maximal voluntary handgrip contraction for 3 min. Two spectral components were analysed: low-frequency component reflecting sympathetic efferent activity and high-frequency power (HFnu) reflecting parasympathetic modulation. In addition, a normalized low-frequency power (LFnu) and HFnu were analysed. Genotypes were determined by polymerase chain reaction followed by agarose gel electrophoresis. Results: There were no differences in baseline measurements among groups. The absolute level of LFnu throughout handgrip exercise was significantly lower in Glu 9 /Glu 9 subjects compared with other genotypes, while the decline of absolute HFnu was significantly smaller compared with Glu 12 /Glu 12 genotype. Conclusion: These findings suggest that 12Glu9 deletion polymorphism of the a 2B -AR gene (Glu 9 /Glu 9 genotype) might result in reduced autonomic responsiveness by altering cardiac sympathetic and vagal function during sustained handgrip exercise in normotensive obese women.

show abstract

Identification of a polymorphic glutamic acid stretch in the α2b-adrenergic receptor and lack of linkage with essential hypertension

Cited by 39 publications

References 35 publications

Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Functional Variant in the α _2B Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension

α2B-Adrenergic receptor deletion polymorphism and cardiac autonomic nervous system responses to exercise in obese women

Contact Info

Product

Resources

About

Identification of a polymorphic glutamic acid stretch in the α2b-adrenergic receptor and lack of linkage with essential hypertension

Cited by 39 publications

References 35 publications

Genetic Variation at the Human α 2B -Adrenergic Receptor Locus

Genetic Variation at the Human α 2B -Adrenergic Receptor Locus

Functional Variant in the α 2B Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension

α2B-Adrenergic receptor deletion polymorphism and cardiac autonomic nervous system responses to exercise in obese women

Contact Info

Product

Resources

About

Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Functional Variant in the α _2B Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension