Influence of Genotype on p2Agonist Effects

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ADRB2 is the gene that codes for the p2-AR. This is a single exon on chro-mosome-5 with several single base polymorphisms, of which two have been associated with altered clinical outcomes: the substitution of (i) glycine for arginine at position 16 (gly-16 and arg-16, respectively) and (ii) glutamic acid for glutamine at position 27 (glu-27 and gln-27, respectively). Lung tissue has been used in vitro to investigate the role of these genotypes, but conflicting results have been published. For example, it has been reported that the gly-16 genotype is associated with increased p2-AR desen-sitization (138,139), but those findings have not been reproduced by other investigators (140). Similarly, the glu-27 genotype has been reported both to protect against desensitization (138,139) and to increase desensitization (141). These differences may be explained by differences in the cell culture and experimental techniques used. Additionally, the possible influence of ADRB2 haplotypes (the combination of alleles at two different sites) on p2-AR function may have been important.

The importance of these genotypes has been assessed in asthma in vivo. The gly-16 genotype is associated with a reduced bronchodilator response both in children (142) and adults (143). It has been proposed that these findings are due to excessive "endogenous" p2-AR down-regulation in subjects with the gly-16 genotype, so that inhaled p-agonists have less effect (144). Tan et al. (84) demonstrated that the gly-16 genotype is associated with increased bronchodilator tolerance after regular dosing with formo-terol (145). However, the sample size was small, with only four homozygous arg-16 subjects. These findings were not replicated using salmeterol in a placebo-controlled crossover study involving 20 subjects: 10 glu-16 homozygotes and 10 arg-16 homozygotes (146). There was no influence of genotype on bronchodilator response or bronchoprotection after two-weeks treatment. A lack of association between genotype (either at position 16 or 27) and the degree of bronchoprotection was also observed after a single dose of formoterol (147). However, a larger retrospective analysis suggests that the arg-16 genotype is associated with reduced bronchoprotection. Furthermore, in patients with the arg-16 genotype this effect appears to be greater for formoterol compared to salmeterol (61). The conflicting results of these studies can be explained by small sample sizes, differing study designs, and possible haplotype influences. Nevertheless, the existing data suggests that the gly-16 genotype is associated with reduced bronchodilator response, while the arg-16 genotype is associated with reduced bronchoprotection.

The most important issue in clinical practice is the influence of genotypes on long-term asthma control. A retrospective analysis by Taylor et al. (148) demonstrated that in 108 patients being treated with regular ICS and albuterol, only homozygous arg-16 subjects were predisposed to increased

Total

* p = 0.003 versus Gly/Arg t p = 0.033 versus Gly/Gly

Minor p - 0.03 versus Gly/Arg

■ Salbutamol

□ Salmeterol ro

* p = 0.003 versus Gly/Arg t p = 0.033 versus Gly/Gly

Minor p - 0.03 versus Gly/Arg

■ Salbutamol

□ Salmeterol

Gly/Gly Gly/Arg Arg/Arg All

Figure 9 The effect of genotype on exacerbation rates during regular dosing for 24 weeks with salbutamol or salmeterol. Increased exacerbation rates were observed in arg-16 homozygous subjects during regular salbutamol therapy. Source: From Ref. 148.

Major

* p - 0.002 versus Gly/Arg t p = 0.020 versus Gly/Gly tp = 0,005 versus Arg/Arg placebo

Gly/Gly Gly/Arg Arg/Arg All

Gly/Gly Gly/Arg Arg/Arg All

Gly/Gly Gly/Arg Arg/Arg All

Figure 9 The effect of genotype on exacerbation rates during regular dosing for 24 weeks with salbutamol or salmeterol. Increased exacerbation rates were observed in arg-16 homozygous subjects during regular salbutamol therapy. Source: From Ref. 148.

exacerbation rates (Fig. 9). In contrast, there was no difference between genotypes when the same patients were given salmeterol instead of albuterol. A retrospective analysis of 190 patients randomized to receive albuterol regularly or as needed found that there was a decline in lung function, presumably due to desensitization, only in arg-16 homozygotes who took regular treatment (149). This study included genotype assessment of positions 16 and 27, giving nine potential haplotypes. Thus, although the overall study size was large, the number of patients with each haplotype was relatively small. It is clear that further larger studies, preferably prospective in design, are needed to address genotype and haplotype influences on clinical outcomes such as exacerbation rates during long-term p-agonist therapy.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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