Studies have suggested that asthma patients with a specific genetic makeup, or genotype, might respond less well to certain treatments than those with a different genotype. But an Article published in this week's edition of the Lancet shows that patients with either genotype respond to combination treatment with longacting β2 agonists plus moderate-dose inhaled corticosteroids, and that this treatment should be continued for these patients. The Article is written by Dr Michael E Wechsler, Brigham and Women's Hospital, Boston, MA, USA, and colleagues from the National Institutes of Health Asthma Clinical Research Center, USA.
The genotype variation concerned relates to the β2-adrenergic receptor—the receptor that asthma bronchodilators bind to in order to exert their effects. Some studies suggest that patients with the amino-acid makeup arginine-arginine (Arg-Arg) at a certain position in this receptor (B16 Arg/Arg) benefit less from treatment with longacting β2 agonists such as salmeterol and inhaled corticosteroids than do those with the makeup glycine-glycine (B16 Gly/Gly). The authors investigated whether there is a genotype-specific response to treatment with a longacting β2 agonist in combination with an inhaled corticosteroid.
In this randomised controlled trial, adult patients with moderate asthma were enrolled in pairs of similar lung capacity and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were assigned to receive inhaled longacting β2 agonist (salmeterol 50 μg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. An inhaled corticosteroid (hydrofluoroalkane beclometasone 240 μg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF)—a standard measure of lung function.
The team found that PEF did not differ between treatment groups, with both recording very similar lung function. However, responsiveness to methacholine was also assessed and revealed that Arg-Arg patients did not benefit from addition of salmeterol with respect to this important marker of airway hyper-responsiveness, whereas Gly-Gly patients did*. Another interesting finding was that African-Americans with the Arg-Arg genotype (20% of African Americans) did not improve with respect to lung function with the addition of the long acting β2 agonist to the inhaled corticosteroid the way African –American Gly-Gly subjects did. This may modify the risk benefit ratio of longacting beta agonists in this population.
The authors conclude: "The LARGE study showed that B16 Arg/Arg and B16 Gly/Gly patients with asthma had similar and substantial improvements in airway function when salmeterol was added to inhaled corticosteroid therapy. These findings provide reassurance that, in the general population, patients should continue to be treated with longacting β2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. However, we need to further investigate the importance of the genotype-differentiated response in airway reactivity favouring Gly/Gly participants, as well as the finding that African-Americans with the the Arg/Arg genotype might not benefit from treatment with salmeterol."
In an accompanying Comment, Dr H William Kelly, University of New Mexico Health Sciences Center, Albuquerque, NM, USA, says: "Studies of single-nucleotide polymorphisms are probably limited because response is mediated by numerous factors and interactions. Genome-wide association studies currently underway that can evaluate the interactions between phenotypes and several genetic polymorphisms and their combinations, as well as other response elements, are more likely to provide clinically significant findings."
Dr Michael E Wechsler, Brigham and Women's Hospital, Boston, MA, USA. T) 1-617-2854987 E) mwechsler@partners.org
Dr H William Kelly, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. T) +1 505-272-3658 E) hwkelly@salud.unm.edu
For full Article and Comment, see: http://press.thelancet.com/largefinal.pdf
Note to editors: *Methacholine challenge is a way to assess airway hyperresponsiveness, or twitchiness of the airways. When one inhales the irritant methacholine, lung function declines in patients with asthma, and remains stable in non-asthma patients. It is measured by looking at the provocative dose of methacholine required to cause a 20% decline in lung function (the PC20). In this study, when salmeterol was given to gly/gly patients, the PC20 doubled (the dose of methacholine required doubled.) In arg-arg patients, there was no benefit—adding salmeterol resulted in no change in PC20 compared with placebo, ie, there was no benefit in airway hyper-responsiveness.
Journal
The Lancet