Although the long-acting β-agonist salmeterol improves asthma control in non–genotype-stratified groups (9
), our current analyses, from two separate trials, suggest that in a subset of patients with asthma (the one-sixth of patients who are B16Arg/Arg), airway function and indices of asthma control do not improve to the same degree with salmeterol treatment, either with or without concurrent ICS use. These results are similar to those of previous studies that suggested that regular use of the short-acting β-agonist albuterol may produce adverse effects in B16Arg/Arg subjects with asthma (6
) and that they may benefit by withdrawal from β-agonists (6
In the first trial (SOCS), in which subjects with milder asthma had their ICS treatment withdrawn and were treated instead with salmeterol or placebo, B16Arg/Arg subjects who received salmeterol alone, compared with placebo, had a significantly worse response with respect to a.m
. PEF compared with B16Gly/Gly individuals. In the second trial (SLIC), in which subjects with more severe asthma received salmeterol while remaining on ICS, a.m
. PEF in B16Gly/Gly subjects improved significantly compared with B16Arg/Arg subjects. In this cohort, there were also genotype-specific differences in FEV1
, rescue albuterol use, and symptoms. In both trials, similar to a prior retrospective analysis (6
), heterozygotes harboring the B16Arg/Gly genotype responded in a manner similar to that of B16Gly/Gly subjects.
It is clear from our data that B16Arg/Arg subjects do not do as well as B16Gly/Gly subjects when treated with salmeterol. Although we were only able to detect genotype-specific differences in a.m
. PEF and a trend toward a difference in PEF variability in our first cohort, the fact that we observed differences in symptoms and medication use in our second cohort suggests that the effect is not restricted to PEF alone. Furthermore, the genotype-specific differences in a.m
. PEF in these two trials (51.4 and 36.8 L/min differences in a.m
. PEF in the SOCS and SLIC trials, respectively) were substantial and were similar in both magnitude and pattern to those reported with short-acting β-agonists in retrospective studies (6
Figure E1), as well as in a randomized prospective trial (8
). Smaller differences in a.m
. PEF (e.g., < 20 L/min) have been associated with clinically important changes in asthma control (32
). Of interest, we did not observe a significant genotype-specific difference in p.m.
PEF or in some of the other outcomes. This may relate to the sample size or to changes in duration of salmeterol effect with continued use (34
The reason that B16Arg/Arg patients failed to achieve as salutary a response to salmeterol as B16Gly/Gly subjects is unclear. Some have speculated that it may be due to differences in receptor down-regulation between polymorphic variants of β2AR (35
) or to genotype-specific difference in loss of bronchoprotection (36
). Others have suggested that persistent β2AR-induced activation of extracellular signal-regulated kinases in airway smooth muscle cells contributes to mitogenesis and exaggerated inflammatory cytokine expression (37
). These effects may be affected by polymorphisms of the receptor. A recent report that alterations in the β2AR gene can affect the signaling and function of other receptors that control airway contractility (38
) suggests an additional mechanism. These mechanisms might explain the slow onset reported here and in our prior findings with short-acting β-agonists (6
) and are consistent with an apparent initial salutary response to salmeterol in B16Arg/Arg patients in the SLIC trial. Furthermore, it is also possible that the B16Arg/Arg polymorphism may be in linkage disequilibrium with the true etiologic polymorphism. In this regard, similar to recent findings that failed to demonstrate an association between acute bronchodilator response and β2
-adrenoceptor haplotype in patients with asthma (39
), we were unable to detect stronger associations using combinations of additional polymorphisms (haplotypes) in the gene. Last, we cannot rule out the possibility that the genotype-specific effects associated with salmeterol are related to a secondary increase in albuterol use in B16Arg/Arg patients. However, the fact that B16Arg/Arg subjects receiving salmeterol used more albuterol than B16Gly/Gly subjects suggests that they had sufficient symptoms to warrant the increased use of this rescue medication.
Prior studies with short-acting β-agonists have demonstrated an increased risk of asthma exacerbations in B16Arg/Arg subjects receiving albuterol on a regular basis (7
). Although salmeterol appears to have a negative impact in B16Arg/Arg patients not receiving ICS, the question of whether salmeterol is indeed deleterious (with declining lung function or increasing exacerbations, as occurs with short-acting β-agonists) in these subjects when used with ICS is less clear from our data. In the SOCS trial, when ICS were discontinued, salmeterol in and of itself was associated with a decline in a.m.
PEF compared with placebo in B16Arg/Arg subjects. In SLIC, although the outcomes trended in a negative direction, the decline did not reach statistical significance. Whether our failure to demonstrate a deleterious effect in SLIC may have been due to the small number of B16Arg/Arg patients in this arm or due to the concurrent use of ICS is unclear.
This documented decline in B16Arg/Arg subjects treated with salmeterol compared with placebo in SOCS raises the question of whether the reports of a possible small increased rate of death and/or severe deteriorations in asthma symptoms in subjects receiving salmeterol (12
) (or other long-acting β-agonists such as formoterol [40
]) are related to the effect we observed by genotype. Of note, there were no such severe deteriorations or deaths observed in our studies. Although such potential β-agonist–related adverse effects were reported to occur more frequently in African Americans (13
), who have an increased frequency of B16Arg/Arg (41
), and although ethnic-specific pharmacogenetic differences have been demonstrated in individuals with different β-adrenergic genotypes (42
), it is important to note that inclusion of African Americans did not bias our study finding. There were no more than two African-American subjects of each genotype in any arm of our studies ( and ), and their exclusion had little effect on our results. Furthermore, we did not observe differences between the genotypes in rates of asthma exacerbation as has been previously observed with short-acting β-agonists (7
). This may be due to the fact that the rate of exacerbations was not high enough in our cohorts to detect such a difference.
In summary, in two separate trials, including one with concomitant ICS treatment, we demonstrated that B16Arg/Arg patients have a substantially diminished therapeutic response to the regular use of salmeterol, compared with those harboring the B16Gly/Gly genotype. In fact, in the setting of ICS withdrawal, B16Arg/Arg patients may experience adverse effects with salmeterol. These findings suggest that B16Arg/Arg patients (~ one-sixth of whites and ~ one-fifth of African Americans) might benefit from alternate asthma treatment strategies. Before implementation, our findings would benefit from prospective confirmation and further investigation of concurrent factors that might affect this altered response.