Influence of genetic variants on the response to long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) and combination therapies in patients with chronic obstructive pulmonary disease (COPD): a systematic review

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory disease in which patients may differ in terms of clinical course and response to drug treatment. Genetic variability may contribute to these differences by influencing drug response and clinical outcomes. This systematic review aimed to summarize the available evidence on the association between genetic variants and clinical outcomes or treatment response in patients with COPD receiving LABA- and/or LAMA-based therapies, as well as pharmacogenetic response to combination inhalants. Methods A systematic search was conducted in the PubMed and Scopus databases, as well as in the gray literature, for studies published between 2015 and 2026. Studies were considered eligible if they included adults with COPD receiving LABA and/or LAMA treatment, including combination regimens, and evaluated genetic variants in relation to therapeutic response. Additionally, studies focusing on disease phenotypes rather than specific pharmacogenetic markers were also included. Study selection and data extraction were performed by two independent reviewers. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) and Cochrane Risk of Bias 2 (RoB 2) tool. Results A total of 51 records were identified, and eight studies were included. Genetic variants in the ADRB2, FAM13A, SUMF1, MAPK8, AZU1, CSE1L , and CCL2 genes were investigated in relation to lung function, disease severity, and treatment response. ADRB2 variants (rs1042713, rs1042714, and rs1800888) were associated with lung function and exacerbation risk, although results regarding bronchodilator treatment response were inconsistent. Regarding other genetic variants, SUMF1 rs793391 emerged as a candidate variant in patients treated with combined bronchodilators and inhaled corticosteroids (ICS). However, these findings are based on limited data and currently lack independent replication, warranting cautious interpretation. Furthermore, findings from large GWAS revealed novel candidates associated with treatment outcomes, though these results were not replicated in subsequent independent enome-Wide Association Study analyses. Due to the limited number of studies and considerable heterogeneity, no meta-analysis was performed. Conclusion This review highlights the latest advances in COPD pharmacogenetics by synthesizing available evidence on patient responses to bronchodilators and corticosteroids. By mapping key methodological factors, the review provides valuable insight into optimizing future research. Systematic Review Registration www.crd.york.ac.uk/prospero/ , identifier CRD420261392469.