Abstract
One of the gene polymorphisms often studied in asthmatic patients is the β2 adrenergic receptor (ADRβ2). Even though in the Venezuelan Mestizo population there is a high incidence of asthma, there are no direct reports of ADRβ2 gene polymorphism, and treatment response. The aim of this study was to assess, in this population, the gene frequency of ADRβ2 polymorphisms at codons 16 Arg/Gly and 27 Gln/Glu, allergen sensitization, and its relationship to bronchodilator response. Purified genomic DNA was obtained form 105 Mestizo asthmatic and 100 Mestizo healthy individuals from Venezuela. The two polymorphisms were assessed by PCR-RFLP. Patient sensitization to aeroallergens and their response to bronchodilatation were correlated. Significant differences between patients and controls were recorded in: 1) the prevalence of Arg/Arg at codon 16 (28.6% in patients vs. 47% in controls, P<0.01), 2) the frequency of heterozygotes Arg/Gly (55% in patients vs. 35% in controls, P<0.01). Conversely, no differences in polymorphism frequencies were found at codon 27. The haplotypes Arg/Gly-Gln/Gln were more common in patients than controls (P <0.01), whereas the Arg/Arg-Gln/Glu combination prevailed in the control group (P<0.01). The Arg/Gly and Gln/Glu genotypes were associated with better responses after salbutamol. The asthmatic homozygotes Arg/Arg have higher sensitivity to aeroallergens. The difference in Arg/Arg frequency between groups suggests that this could be a protective genotype although the asthmatic group had a higher sensitivity to aeroallergens. The asthmatic heterozygotes had better bronchodilator responses than the homozygotes.
Highlights
Asthma is a highly prevalent and complex disease in which multiple interacting genes and environmental factors are involved[1]
The most common polymorphisms of the adrenergic β-2 receptors (ADRβ2) are at codons 16 and 27 and several studies have suggested that these polymorphisms have a modulatory effect on asthma severity and response to therapy
The results of our study showed that the frequency of Arg/Arg at amino acid 16 was higher in the Venezuelan Mestizo normal population and the Arg/Gly heterozygous was more prevalent in our asthmatic population contrasting with reports on Caucasian or Asian populations[8,9,10,17]
Summary
Asthma is a highly prevalent and complex disease in which multiple interacting genes and environmental factors are involved[1]. It has been shown that: 1) In the LARGE multicenter study, asthmatics with Arg/Arg homozygous genotype, receiving inhaled corticosteroids, experience no change in hyperresponsiveness status even when long acting β2 agonists were used8; 2) a combination of salmeterol plus inhaled corticosteroid in the patients Gly/Gly, at amino acid 16 increased 2.4 times the PC20, resulted in decreased bronchial hyperresponsiveness5,8; 3) the Gly16/Gln[27] haplotype was inversely associated with hyperresponsiveness to methacholine, while the Arg16/Gln[27] haplotype was associated with a greater degree of hyperresponsiveness[9], and 4) children homozygous and heterozygous for Arg[16] had higher bronchodilator responses than Gly[16] homozygotes patients[10] These findings correspond to Caucasians, in Venezuela there is a high prevalence of asthma and a large Mestizo population which seem to have a high genetic segregation[11,12,13]. The asthmatic heterozygotes had better bronchodilator responses than the homozygotes
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