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 χ2 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.

Figure 1

Complete association of the ADRB2 polymorphisms [Arg16Gly (c.46A > G) and Gln27Glu (c.79C > G)] with asthma risk. (A) Gene, mRNA and protein representation; (B) polymorphism analyses (green); (C) haplotype analyzed (purple); (D) haplotype groups analyzed (red).

Figure 2

Multifactor dimensionality reduction test for the Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene in Asthma patients. A. Distribution of patients according to different genotype combinations for the clustering of Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene. Combinations of high risk are in gray and low risk are in white. The number in the figure represents the patients with a given genotype combination. For example, in the first square, 14 asthma patients (left column) and five healthy patients (right column) have the following genotype: AA for the Arg16Gly polymorphism and CC for the Gln27Glu polymorphism. In this case, the first column in each square represents the asthma patient group, and the second column represents healthy subjects. B. Dendrogram of the polymorphism interactions with respect to asthma presence. The same color in this case indicates linkage between the analyzed polymorphisms. C. Graph of entropy measuring the power of different polymorphisms and the interactions between them for the gene analyzed to explain the polymorphism-polymorphism association with asthma occurrence. The association is represented by 9.87% for the Arg16Gly polymorphism and 24.36% for the Gln27Glu polymorphism. The interaction between the polymorphisms accounts for -9.28% of the association. The protective genotypes in our samples are CG (for the Gln27Glu polymorphism) and AG or GG (for the Arg16Gly polymorphism).