beta2 adrenoceptor promoter polymorphisms: extended haplotypes and functional effects in peripheral blood mononuclear cells

Lipworth, Brian J.; Koppelman, Gerard H.; Wheatley, A; Jeune, I Le; Coutie, Wendy J.; Meurs, Herman; Kauffman, Hf; Postma, Dirkje S.; Hall, Ian P.

doi:10.1136/thorax.57.1.61

Cited by 50 publications

(44 citation statements)

References 18 publications

(20 reference statements)

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“…In-vitro evidence indicates that different haplotypes confer different receptor behaviour, and preliminary evidence suggests that haplotype pairs alter response to salbutamol in asthmatics (Drysdale et al 2000). In contrast, we found no association between levels of 2 -adrenoceptor expression or cyclic AMP responses in circulating peripheral blood mononuclear cells and different haplotypes (Lipworth et al 2002). In view of these data, a definitive, large-scale prospective study assessing the effects of 2 -adrenoceptor haplotypes on the response to 2 -agonists is required before the stratification of treatment according to genotype at a population level can be evaluated.…”

Section: Relevant Treatment-responsive Genes and Asthmacontrasting

confidence: 52%

Personalised prescribing for asthma - is pharmacogenetics the answer?

Dewar

Hall

2003

Journal of Pharmacy and Pharmacology

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An individual's response to anti-asthma medication is likely to arise from a complex interaction between social, environmental and inherited factors. Studies indicate that genetic factors may account for 60-80% of the heterogeneity in treatment responsiveness in asthmatics. Identifying the genetic variants responsible may potentially lead to the development of novel treatments, improved effectiveness in the use of existing treatments and better prediction of efficacy in phase II and III trials. This article will briefly outline the current methods of identifying relevant treatmentresponsive genes and their genetic variants. The pharmacogenetics of the main asthma treatment groups will then be reviewed in detail. Finally, the impact of pharmacogenetics on the pharmaceutical industry, and clinical practice in the future will be discussed.

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Section: Relevant Treatment-responsive Genes and Asthmacontrasting

confidence: 52%

Personalised prescribing for asthma - is pharmacogenetics the answer?

Dewar

Hall

2003

Journal of Pharmacy and Pharmacology

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“…In an examination of ex vivo (lymphocytes) and in vivo (bronchoprotection) function of ␤ 2 -ARs in asthmatic patients, Lipworth et al (1999b) assessed ␤ 2 -AR binding density, binding affinity, basal and isoproterenol-stimulated cAMP response, and the protective effect of a single dose of inhaled formoterol against methacholine-induced bronchoconstriction and found that ␤ 2 -AR polymorphisms at positions 16 and 27 did not influence cAMP response or functional antagonism. Subsequent work by the same group using peripheral blood mononuclear cells from 96 individuals with asthma showed that no single polymorphism (in particular those at positions 16 and 27) or haplotype was correlated with levels of ␤ 2 -AR expression or cAMP response to isoproterenol (Lipworth et al, 2002). Thus, taken together, some recent findings with native human cells contrast with data from transfected cell systems and provide less consistent evidence that Gly16, alone or together with Glu27, is necessarily associated with greater desensitization or with a decrease in agonistpromoted responses.…”

Section: Most Common Haplotypes and Frequencies (ͼ5%) In Several Popumentioning

confidence: 99%

Autonomic Nervous System Pharmacogenomics: A Progress Report

2004

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“…By contrast, a study using lymphocytes isolated from asthmatics demonstrated that there was no association between the polymorphism at -47 and β 2 -adrenoceptor expression [17]. While lymphocytes were used in this study as a representation of lung β 2 -adrenoceptors, it is known that the behaviour and expression of β 2 -adrenoceptors can be influenced by the tissue or cell in which the receptor is expressed [25][26][27].…”

Section: Discussionmentioning

confidence: 92%

“…An influence of polymorphisms on β 2 -adrenoceptor expression has been assessed in transfected cells and lymphocytes with equivocal outcomes [11][12][13][14][15]17]. The aim of the present study was to perform a comprehensive analysis of the influence of polymorphisms across ADRB2 on β 2 -adrenoceptor expression in human lung tissue.…”

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confidence: 99%

Influence of β2-adrenoceptor gene polymorphisms on β2-adrenoceptor expression in human lung

Kay

Suvarna

Scola

et al. 2010

Pulmonary Pharmacology & Therapeutics

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Background: The aim of the present study was to establish whether polymorphisms, especially those within the promoter region, of the β 2 -adrenoceptor gene (ADRB2) influence β 2 -adrenoceptor expression in human lung. Methods:The density of β-adrenoceptors in human lung tissue (n=88) was determined by saturation binding using the radioligand, iodinated cyanopindolol. Discrimination of β 1 -and β 2 -adrenoceptors was determined using the highly selective β 1 -adrenoceptor antagonist, CGP20712A. Genotype was determined at 5 positions of ADRB2 previously reported as polymorphic. Potential influences of single nucleotide polymorphisms (SNPs) within the promoter region (-367, -47) and coding block (46, 79, 491) of ADRB2 on β 2 -adrenoceptor expression were investigated. Results:The density of β 2 -adrenoceptors was variable among the 88 lung preparations studied ranging from 17 to 177 fmol/mg protein (mean±S.E.M., 72±4 fmol/mg protein).There was no influence of genotype on β 2 -adrenoceptor expression for any of the polymorphisms studied except at position 491. The polymorphism at position 491C>T, leading to a change from thr to ile at amino acid 164, is uncommon. Preparations genotyped as heterozygous (126±15 fmol/mg protein; n=5) expressed significantly (P = 0.0005) higher levels of β 2 -adrenoceptor than those that were homozygous (69±4 fmol/mg protein; n=83). M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS

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beta2 adrenoceptor promoter polymorphisms: extended haplotypes and functional effects in peripheral blood mononuclear cells

Cited by 50 publications

References 18 publications

Personalised prescribing for asthma - is pharmacogenetics the answer?

Personalised prescribing for asthma - is pharmacogenetics the answer?

Autonomic Nervous System Pharmacogenomics: A Progress Report

Influence of β2-adrenoceptor gene polymorphisms on β2-adrenoceptor expression in human lung

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