Association of β<sub>2</sub>‐adrenergic receptor polymorphisms with severe asthma

Holloway, John W.; Dunbar, P. Rod; Riley, Greta; Sawyer, Gillian; Fitzharris, Penny; Pearce, Neil; Gros, Graham Le; Beasley, Richard

doi:10.1046/j.1365-2222.2000.00929.x

Cited by 115 publications

(72 citation statements)

References 22 publications

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“…Holloway et al 26 found that ADRB2 variants were associated with asthma severity; however, that study was based on a small sample. That finding was not replicated in a larger study and a meta-analysis by Hall et al, 6 which included the data from the study by Holloway et al 26 Given the existing evidence, we can speculate that the effect of Arg16 allele is mediated by increasing AHR, 25 which was further accentuated by smoking's leading to wheezing. It could be that these wheezing episodes are attributable to airway hyperreactivity and results in a clinical pattern that supports an asthma diagnosis.…”

Section: Discussionmentioning

confidence: 95%

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

et al. 2008

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Objective-Associations between single-nucleotide polymorphisms in the β2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects β2-adrenergic receptor gene expression and associations of β2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of β2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study.Methods-We fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes.Results-Exposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism-specific results. No associations were found for Glu27Gln.Conclusions-Both in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16-Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of β2-adrenergic receptor gene variants on respiratory health outcomes. In ADRB2, Arg16Gly and Glu27Gln are the 2 most common nonsynonymous single-nucleotide polymorphisms (SNPs). In an in vitro study, Green et al 1 found that the Gly16 allele was more susceptible to agonist-promoted downregulation, and the Glu27 allele was resistant to agonistmediated receptor downregulation; however, subsequent ex vivo and in vivo studies provided inconsistent findings. 2 The majority of the epidemiologic studies have investigated the associations of these 2 SNPs and asthma/wheeze and found inconsistent results. In addition, meta-analyses that pooled data from these studies failed to show any significant associations with asthma; however, these authors could not rule out effects of these SNPs on asthma symptoms. [3][4][5][6] The inconsistencies across studies may have resulted from not taking into account environmental factors that could modulate the receptor activity. Tobacco smoke is 1 such factor that is associated with an increase in AHR and oxidant stress-mediated...

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Section: Discussionmentioning

confidence: 95%

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

et al. 2008

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“…23 PCR-RFLP for b 2 -AR codons 16 and 27 was conducted according to previously described methods, using the NcoI and BbVI restriction enzymes, respectively. 24 The RFLP protocol for b 2 -AR codons 16 and 27 was modified to consist of 20 ml reactions containing 5 ml of PCR product, 5 U of NcoI (for b 2 -AR codon 16) or 3 U of BbVI (for b 2 -AR codon 27), digested for 2 h at 37 1C. Genotypes were scored by two independent investigators.…”

Section: Genotyping Methodsmentioning

confidence: 99%

β-Adrenergic receptor gene polymorphisms and hemodynamic response to dobutamine during dobutamine stress echocardiography

et al. 2008

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Our objective was to determine if b 1 -adrenergic receptor (b 1 -AR) and b 2 -AR gene polymorphisms influence heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) response to dobutamine during dobutamine stress echocardiography (DSE). Patients (n ¼ 163) undergoing clinically indicated DSE were enrolled. Dobutamine doses were titrated from 5 to 40 mg kg À1 min À1 at 3 min intervals and HR, SBP and DBP were measured. Genotypes were determined for b 1 -AR Ser49Gly, b 1 -AR Arg389-Gly, b 2 -AR Arg16Gly and b 2 -AR Gln27Glu polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis, pyrosequencing and single primer extension methods. b 2 -AR Glu27 homozygotes had a greater HR response at the highest dobutamine dose than Gln27 carriers (P ¼ 0.002). b 2 -AR Gly16 homozygotes had a lower HR response during 5-30 mg kg À1 min À1 of the dobutamine infusion protocol compared to Arg16 carriers (P ¼ 0.03). Differences in SBP by b 2 -AR codon 16 genotype and DBP by b 1 -AR codon 389 genotype were found at baseline and were maintained throughout DSE (P ¼ 0.06 and 0.02, respectively). However, the magnitude of SBP and DBP response to dobutamine did not differ significantly by b 2 -AR codon 16 or b 1 -AR codon 389 genotypes, respectively. These data suggest that the four selected b 1 -and b 2 -AR polymorphisms do not substantially influence the magnitude of hemodynamic response to dobutamine during DSE.

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“…The β 2 adrenergic receptor (β 2 AR) is one of the candidate genes most consistently identified as being associated with asthma-related phenotypes Evans et al 2001;Holloway et al 2000;Silverman et al 2003). The Gly16 polymorphism has been associated with asthma severity and lower bronchodilator responsiveness, while the Arg16 allele has been shown to be associated with increased bronchodilator responsiveness (Martinez et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations

et al. 2005

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Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which cases and controls are matched by admixture, can be an appealing and suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments (SAGE). Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV 1 , a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P = 0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers (AIMs) and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, β 2 adrenergic receptor (β 2 AR) and ΔFEF 25-75 , an asthma-related phenotype, as an † Correspondence and reprint requests should be addressed to:

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Association of β₂‐adrenergic receptor polymorphisms with severe asthma

Abstract: We conclude that the polymorphisms of amino acids 16 and 27 of the beta2AR gene are not associated with the development of asthma per se, but that the Gly16 polymorphism may play a role in the pathogenesis of asthma severity.

Cited by 115 publications

References 22 publications

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

β-Adrenergic receptor gene polymorphisms and hemodynamic response to dobutamine during dobutamine stress echocardiography

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations

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Association of β2‐adrenergic receptor polymorphisms with severe asthma

Abstract: We conclude that the polymorphisms of amino acids 16 and 27 of the beta2AR gene are not associated with the development of asthma per se, but that the Gly16 polymorphism may play a role in the pathogenesis of asthma severity.

Cited by 115 publications

References 22 publications

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing

β-Adrenergic receptor gene polymorphisms and hemodynamic response to dobutamine during dobutamine stress echocardiography

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations

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Association of β₂‐adrenergic receptor polymorphisms with severe asthma