Arg16Gly β2-Adrenoreceptor Polymorphism in Severe Eosinophilic Asthma: Implications for Mepolizumab Long-Term Effectiveness and Clinical Remission

<bold>Background:</bold> β₂-adrenoreceptors promote the relaxation of airway smooth muscle and dampen the release of pro-inflammatory mediators by eosinophils. The rs1042713 polymorphism encodes a glycine-to-arginine substitution (Arg16Gly) responsible for enhanced β₂ downregulation. <bold>Aim:</bold> To assess the prevalence of this genetic variant in severe eosinophilic asthmatics and whether it affects the long-term efficacy of mepolizumab and clinical remission. <bold>Material and Methods:</bold> 102 patients with severe eosinophilic asthma (SEA) treated with mepolizumab, 31 mild asthmatics and 20 healthy controls were genotyped. The SEA cohort was followed up to 2 years and clinical data were collected during treatment. Outcomes were compared between genotypes (Arg/Arg, Arg/Gly and Gly/Gly). The achievability of the most common definitions of clinical remission was assessed. <bold>Results:</bold> Arg/Arg homozygotes prevalence was significantly higher in SEA (56.9%) than mild asthmatics [19.4%; OR 5.3 (95% CI 2-14.3), <italic>P</italic>=0.0010] or healthy controls [10%; OR 12 (95% CI 2.5-56.2), <italic>P</italic><0.0001]. During the 24 months of mepolizumab treatment, Arg/Arg patients had higher exacerbation risk [HR 2.3 (95% CI 1.03-5.2), <italic>P</italic>=0.0414] and lower symptom control (ACT ≥20) than Gly/Gly (72.4% vs 100%, <italic>P</italic>=0.0308). After 24 months, Gly/Gly experienced less lung function decline when compared to the best value of the first 12 months of treatment. Using different remission definitions, Gly/Gly demonstrated up to 9 times higher odds of clinical remission at 24 months. <bold>Conclusions:</bold> The rs1042713 polymorphism has a high prevalence in severe eosinophilic asthmatics and might influence mepolizumab effectiveness.