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Asthma: Gln27Glu and Arg16Gly polymorphisms of the beta2-adrenergic receptor gene as risk factors.

ABSTRACT: BACKGROUND:Asthma is caused by both environmental and genetic factors. The ADRB2 gene, which encodes the beta 2-adrenergic receptor, is one of the most extensively studied genes with respect to asthma prevalence and severity. The Arg16Gly (+46A?>?G) and Gln27Glu (+79C?>?G) polymorphisms in the ADRB2 gene cause changes in the amino acids flanking the receptor ligand site, altering the response to bronchodilators and the risk of asthma through complex pathways. The ADRB2 polymorphisms affect beta-adrenergic bronchodilator action and are a tool to identify at-risk populations. OBJECTIVE:To determine the frequency of these two polymorphisms in allergic asthma patients and healthy subjects and to correlate these data with the occurrence and severity of asthma. METHODS:Eighty-eight allergic asthma patients and 141 healthy subjects were included in this study. The ADRB2 polymorphisms were analyzed using the amplification-refractory mutation system - polymerase chain reaction (ARMS-PCR) technique. The statistical analysis was performed with the SPSS 21.0 software using the Fisher's Exact and ?2 tests. RESULTS:The ADRB2 polymorphisms were associated with asthma occurrence. The Arg16Arg, Gln27Gln and Gln27Glu genotypes were risk factors; the odds ratios were 6.782 (CI?=?3.07 to 16.03), 2.120 (CI?=?1.22 to 3.71) and 8.096 (CI?=?3.90 to 17.77), respectively. For the Gly16Gly and Glu27Glu genotypes, the odds ratios were 0.312 (CI?=?0.17 to 0.56) and 0.084 (CI?=?0.04 to 0.17), respectively. The haplotype analysis showed that there were associations between the following groups: Arg16Arg-Gln27Gln (OR?=?5.108, CI?=?1.82 to 16.37), Gly16Gly-Glu27Glu (OR?=?2.816, CI?=?1.25 to 6.54), Arg16Gly-Gln27Glu (OR?=?0.048, CI?=?0.01 to 0.14) and Gly16Gly-Gln27Glu (OR?=?0.1036, CI?=?0.02 to 0.39). The polymorphism Gln27Glu was associated with asthma severity, as the Gln27Gln genotype was a risk factor for severe asthma (OR?=?2.798, CI?=?1.099 to 6.674) and the Gln27Glu genotype was a protective factor for mild (OR?=?3.063, CI?=?1.037 to 9.041) and severe (OR?=?0.182, CI?=?0.048 to 0.691) asthma. CONCLUSIONS:The Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene are associated with asthma presence and severity.

SUBMITTER: de Paiva AC

PROVIDER: S-EPMC3930554 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Asthma: Gln27Glu and Arg16Gly polymorphisms of the beta2-adrenergic receptor gene as risk factors.

de Paiva Ana Carolina Zimiani AC Marson Fernando Augusto de Lima FA Ribeiro José Dirceu JD Bertuzzo Carmen Sílvia CS

Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 20140205 1

<h4>Background</h4>Asthma is caused by both environmental and genetic factors. The ADRB2 gene, which encodes the beta 2-adrenergic receptor, is one of the most extensively studied genes with respect to asthma prevalence and severity. The Arg16Gly (+46A > G) and Gln27Glu (+79C > G) polymorphisms in the ADRB2 gene cause changes in the amino acids flanking the receptor ligand site, altering the response to bronchodilators and the risk of asthma through complex pathways. The ADRB2 polymorphisms affe ...[more]

PMID: 24499171

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Project description:Short-acting inhaled beta2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The beta2-adrenergic receptor (beta2AR) is the target for beta2-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to beta2-agonists.We hypothesized that there are pharmacogenetic interactions between GSNOR and beta2AR gene variants that are associated with variable response to albuterol.We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and beta2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants.Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3'UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P=0.04-0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and beta2AR gene variants and the response to albuterol in Puerto Rican (P=0.03), Mexican (P=0.15) and combined Puerto Rican and Mexican asthmatics (P=0.003). Specifically, GSNOR+17059*beta2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response.Genotyping of GSNOR and beta2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.

Dataset Information

Asthma: Gln27Glu and Arg16Gly polymorphisms of the beta2-adrenergic receptor gene as risk factors.

Publications

Asthma: Gln27Glu and Arg16Gly polymorphisms of the beta2-adrenergic receptor gene as risk factors.

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