Background: beta(2)-adrenergic signaling promotes airway smooth muscle relaxation and limits the release of pro-inflammatory mediators by immune cells. The rs1042713 polymorphism encodes a glycine-to-arginine substitution (Arg16Gly) that enhances beta(2)-receptor downregulation. We investigated the association of this polymorphism with the risk of severe eosinophilic asthma and its impact on the long-term effectiveness of mepolizumab and clinical remission. Methods: Genotypes from 102 patients with severe eosinophilic asthma receiving mepolizumab were compared with those from 31 individuals with mild asthma and 20 healthy controls. The severe-asthma cohort was followed for up to 24 months, and clinical data were collected at baseline and after 3, 6, 12, and 24 months of treatment. Analyses were stratified by Arg/Arg, Arg/Gly, and Gly/Gly genotypes. Results: Each additional Arg16 allele increased the odds of severe eosinophilic asthma by 2.61-fold (95% CI 1.48-4.59; p = 0.0001) relative to mild asthma and by 3.61-fold (95% CI 1.78-7.35; p < 0.0001) relative to healthy controls. Over 24 months of mepolizumab treatment, Arg/Arg patients had an increased risk of exacerbations (HR 2.3 [95% CI 1.03-5.20]; p = 0.0414) and poorer asthma control compared with Gly/Gly patients (ACT >= 20: 72.4% vs. 100%, p = 0.0308). Gly/Gly patients also experienced less decline in lung function. By month 24, each additional Gly16 allele increased the odds of achieving clinical remission by 2.86-fold (95% CI 1.20-6.81; p = 0.0170), defined as no annual exacerbations, no OCS, and ACT >= 20, and by 3.06-fold (95% CI 1.34-6.96; p = 0.0080) when including an FEV1 decline <= 5% from baseline. Conclusions: The Arg16 allele of the rs1042713 polymorphism increases the risk of severe eosinophilic asthma and may reduce the long-term efficacy of mepolizumab, whereas the Gly16 allele appears to confer better outcomes and higher remission rates.
Effect of the Arg16Gly β2-Adrenergic Receptor Polymorphism on Long-Term Mepolizumab Response and Clinical Remission in Severe Eosinophilic Asthma: A Genotype-Stratified, Multicenter Study
Maglio A.;Carrieri I.;Vatrella A.;Triggiani M.;Parente R.;Longobardi V.
2025
Abstract
Background: beta(2)-adrenergic signaling promotes airway smooth muscle relaxation and limits the release of pro-inflammatory mediators by immune cells. The rs1042713 polymorphism encodes a glycine-to-arginine substitution (Arg16Gly) that enhances beta(2)-receptor downregulation. We investigated the association of this polymorphism with the risk of severe eosinophilic asthma and its impact on the long-term effectiveness of mepolizumab and clinical remission. Methods: Genotypes from 102 patients with severe eosinophilic asthma receiving mepolizumab were compared with those from 31 individuals with mild asthma and 20 healthy controls. The severe-asthma cohort was followed for up to 24 months, and clinical data were collected at baseline and after 3, 6, 12, and 24 months of treatment. Analyses were stratified by Arg/Arg, Arg/Gly, and Gly/Gly genotypes. Results: Each additional Arg16 allele increased the odds of severe eosinophilic asthma by 2.61-fold (95% CI 1.48-4.59; p = 0.0001) relative to mild asthma and by 3.61-fold (95% CI 1.78-7.35; p < 0.0001) relative to healthy controls. Over 24 months of mepolizumab treatment, Arg/Arg patients had an increased risk of exacerbations (HR 2.3 [95% CI 1.03-5.20]; p = 0.0414) and poorer asthma control compared with Gly/Gly patients (ACT >= 20: 72.4% vs. 100%, p = 0.0308). Gly/Gly patients also experienced less decline in lung function. By month 24, each additional Gly16 allele increased the odds of achieving clinical remission by 2.86-fold (95% CI 1.20-6.81; p = 0.0170), defined as no annual exacerbations, no OCS, and ACT >= 20, and by 3.06-fold (95% CI 1.34-6.96; p = 0.0080) when including an FEV1 decline <= 5% from baseline. Conclusions: The Arg16 allele of the rs1042713 polymorphism increases the risk of severe eosinophilic asthma and may reduce the long-term efficacy of mepolizumab, whereas the Gly16 allele appears to confer better outcomes and higher remission rates.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
