Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: a systematic review

Background: Long-acting beta2-agonists (LABA) are recommended in asthma therapy, however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma.

Methods: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included.

Results: In total, thirty-three studies were included in this systematic review, eight focused on children (n=6,051). Nineteen studies were clinical trials, while fourteen were observational studies. Studies used different outcomes to define LABA response, e.g. lung function measurements (FEV1 , PEF, MMEF, FVC), exacerbations, quality of life and asthma symptoms. Most studies (n=30) focussed on the ADRB2 gene, encoding the beta2 adrenergic receptor. Thirty studies (n=14,874) addressed ADRB2 rs1042713, 7 ADRB2 rs1042714 (n=1,629) and 3 ADRB2 rs1800888 (n=1,892). The association of ADRB2 rs1042713 and rs180888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focussed on the ADCY9 gene. Five studies and a meta-analysis found increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults.

Conclusions: ADRB2 rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2 rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed.