Pharmacogenetics of Beta-1- and Beta-2-Adrenergic Receptors

Liggett, Stephen B.

doi:10.1159/000028397

Cited by 131 publications

(75 citation statements)

References 29 publications

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“…The beta adrenergic receptors belong to the G-proteincoupled receptor superfamily and mediate some of the physiological actions of catecholamines (noradrenaline and adrenaline) in a variety of tissues (Liggett 2000). Different beta-receptor subtypes have been characterized (Liggett 2000).…”

Section: Discussionmentioning

confidence: 99%

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A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

et al. 2008

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Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related 123Behav Genet (2009) 39:15-23 DOI 10.1007 to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.

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Section: Discussionmentioning

confidence: 99%

“…Different beta-receptor subtypes have been characterized (Liggett 2000). The beta-2 receptor is expressed in the smooth muscle of both the airways and blood vessels (to a lesser extent), and also can be found in the CNS (Hillman et al 2005b).…”

Section: Discussionmentioning

confidence: 99%

A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

et al. 2008

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“…7,8 Several polymorphisms of the human ADRB2 gene have been described. 9,10 Among these, three common single-nucleotide polymorphisms (SNPs) result in the substitution of an amino acid. One is located at codon 16, substituting arginine for glycine (Arg16Gly).…”

Section: Introductionmentioning

confidence: 99%

Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

et al. 2006

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Background and aims: Obesity is associated with a blunted b-adrenoceptor-mediated lipolysis and fat oxidation. We investigated whether polymorphisms in codon 16, 27 and 164 of the b 2 -adrenoceptor gene (ADRB2) and exon 10 of the G protein b 3 -subunit gene (GNB3) are associated with alterations in in vivo lipolysis and fat oxidation. Design and methods: Sixty-five male and 43 female overweight and obese subjects (body mass index (BMI) range: 26.1-48.4 kg/m 2 ) were included. Energy expenditure (EE), respiratory quotient (RQ), circulating free fatty acid (FFA) and glycerol levels were determined after stepwise infusion of increasing doses of the non-selective b-agonist isoprenaline (ISO). Results: In women, the Arg16 allele of the ADRB2 gene was associated with a blunted increase in circulating FFA, glycerol and a decreased fat oxidation during ISO stimulation. In men, the Arg16 allele was significantly associated with a blunted increase in FFA but not in glycerol or fat oxidation. Conclusion: These results suggest that genetic variation in the ADRB2 gene is associated with disturbances in in vivo b-adrenoceptor-mediated lipolysis and fat oxidation during b-adrenergic stimulation in overweight and obese subjects; these effects are influenced by gene-gender interactions.

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“…78 ␤ 1 -and ␤ 2 -adrenergic receptors increase cardiac inotropy and chronotropy, the ␤ 1 -receptor being the dominant subtype. 79 In heart failure, chronic sympathetic activation leads to selective downregulation of ␤ 1 -adrenergic receptors and uncoupling of ␤ 1 -and ␤ 2 -adrenergic receptors, markedly blunting both signaling pathways. 78 Therefore, one may hypothesize that genetic variants of adrenergic receptors play a role in heart failure.…”

Section: Sympathetic Systemmentioning

confidence: 99%

Genetic polymorphisms and heart failure

Bleumink

Schut

Sturkenboom

et al. 2004

Genetics in Medicine

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Heart failure is a complex clinical syndrome. There is evidence for a genetic contribution to the pathophysiology of heart failure. Considering the fundamental role of neurohormonal factors in the pathophysiology and progression of cardiac dysfunction and hypertrophy, variants of genes involved in this system are logical candidate genes in heart failure. In this report, genetic polymorphisms of the major neurohormonal systems in heart failure will be discussed. Studies on polymorphisms of the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous polymorphisms that may be involved in the development or phenotypic expression of heart failure will be reviewed. Research on left ventricular hypertrophy is also included. The majority of genetic association studies focused on the ACE I/D polymorphism.Initial genetic associations have often been difficult to replicate, mainly due to problems in study design and lack of power. Promising results have been obtained with genetic polymorphisms of the RAAS and sympathetic system.Considering the evidence so far, a modifying role for these polymorphisms seems more likely than a role of these variants as susceptibility genes. Besides the need for larger studies to examine the effects of single nucleotide polymorphisms and haplotypes, future studies also need to focus on the complexity of these systems and study Heart failure is a complex clinical syndrome with high morbidity and mortality. 1,2 Impairment of cardiac function activates compensatory neurohormonal mechanisms, which at a later stage may accelerate progression of heart failure. 3 Coronary heart disease and hypertension are major underlying causes of heart failure. Other frequent underlying conditions include valvular heart disease and idiopathic dilated cardiomyopathy. It is difficult to predict who will develop heart failure in response to myocardial injury. Racial differences in occurrence and outcome of heart failure 4,5 and heritability estimates of variability in left ventricular mass of 28% to 65% 6,7 suggest a genetic contribution to the pathophysiology of left ventricular remodeling and heart failure.Many studies have been published on the role of single gene mutations in (familial) cardiomyopathies. 8,9 These Mendelian traits are by nature rare, and although important at an individual level and for the understanding of disease mechanisms, are of limited significance in terms of prediction of heart failure occurrence in the population. 10 Moreover, in patients with identical gene mutations clinical manifestations of cardiomyopathy may differ. This suggests that probably also environmental and/or other genetic factors play a role.In this report, genetic polymorphisms of major neurohormonal systems involved in the pathophysiology of heart failure will be discussed, including the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous...

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Pharmacogenetics of Beta-1- and Beta-2-Adrenergic Receptors

Cited by 131 publications

References 29 publications

A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

Genetic polymorphisms and heart failure

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