Arg16Gly β2－肾上腺素能受体基因多态性对重症嗜酸粒细胞性哮喘患者美泊利珠单抗长期疗效及临床缓解的影响：一项基于
2025/10/11
摘要
背景：β2－肾上腺素能信号通路可促进气道平滑肌松弛并限制免疫细胞释放促炎介质。rs1042713基因多态性编码甘氨酸至精氨酸的替换（Arg16Gly），该变异可增强β2－受体的下调。我们探讨了该多态性与重症嗜酸粒细胞性哮喘风险的关系及其对美泊利珠单抗长期疗效和临床缓解的影响。
方法：研究比较了102例接受美泊利珠单抗治疗的重症嗜酸粒细胞性哮喘患者与31例轻度哮喘患者及20例健康对照者的基因型。对重症哮喘队列进行了长达24个月的随访，并在基线及治疗后的第3、6、12和24个月收集临床数据。分析按Arg/Arg、Arg/Gly和Gly/Gly基因型进行分层。
结果：相对于轻度哮喘患者，每增加一个Arg16等位基因，患重症嗜酸粒细胞性哮喘的风险增加2.61倍（95% CI 1.48-4.59；p = 0.0001）；相对于健康对照，风险增加3.61倍（95% CI 1.78-7.35；p < 0.0001）。在24个月的美泊利珠单抗治疗期间，与Gly/Gly基因型患者相比，Arg/Arg基因型患者急性加重风险更高（HR 2.3 [95% CI 1.03-5.20]；p = 0.0414），且哮喘控制更差（ACT评分 ≥ 20分者：72.4% vs. 100%， p = 0.0308）。Gly/Gly基因型患者的肺功能下降幅度也更小。至第24个月时，每增加一个Gly16等位基因，实现临床缓解（定义为无年度急性加重、无需口服糖皮质激素且ACT评分 ≥ 20分）的几率增加2.86倍（95% CI 1.20-6.81；p = 0.0170）；若将第一秒用力呼气容积较基线下降 ≤ 5% 纳入缓解标准，则几率增加3.06倍（95% CI 1.34-6.96；p = 0.0080）。
结论：rs1042713基因多态性的Arg16等位基因会增加重症嗜酸粒细胞性哮喘的风险，并可能降低美泊利珠单抗的长期疗效；而Gly16等位基因似乎预示着更好的治疗结局和更高的临床缓解率。
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
Santi, Nolasco; Evelina, Fagone; Raffaele,
Abstrast
BACKGROUND: β(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 β(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 FEV(1) decline ≤ 5% from baseline.
CONCLUSION: 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.
背景：β2－肾上腺素能信号通路可促进气道平滑肌松弛并限制免疫细胞释放促炎介质。rs1042713基因多态性编码甘氨酸至精氨酸的替换（Arg16Gly），该变异可增强β2－受体的下调。我们探讨了该多态性与重症嗜酸粒细胞性哮喘风险的关系及其对美泊利珠单抗长期疗效和临床缓解的影响。
方法：研究比较了102例接受美泊利珠单抗治疗的重症嗜酸粒细胞性哮喘患者与31例轻度哮喘患者及20例健康对照者的基因型。对重症哮喘队列进行了长达24个月的随访，并在基线及治疗后的第3、6、12和24个月收集临床数据。分析按Arg/Arg、Arg/Gly和Gly/Gly基因型进行分层。
结果：相对于轻度哮喘患者，每增加一个Arg16等位基因，患重症嗜酸粒细胞性哮喘的风险增加2.61倍（95% CI 1.48-4.59；p = 0.0001）；相对于健康对照，风险增加3.61倍（95% CI 1.78-7.35；p < 0.0001）。在24个月的美泊利珠单抗治疗期间，与Gly/Gly基因型患者相比，Arg/Arg基因型患者急性加重风险更高（HR 2.3 [95% CI 1.03-5.20]；p = 0.0414），且哮喘控制更差（ACT评分 ≥ 20分者：72.4% vs. 100%， p = 0.0308）。Gly/Gly基因型患者的肺功能下降幅度也更小。至第24个月时，每增加一个Gly16等位基因，实现临床缓解（定义为无年度急性加重、无需口服糖皮质激素且ACT评分 ≥ 20分）的几率增加2.86倍（95% CI 1.20-6.81；p = 0.0170）；若将第一秒用力呼气容积较基线下降 ≤ 5% 纳入缓解标准，则几率增加3.06倍（95% CI 1.34-6.96；p = 0.0080）。
结论：rs1042713基因多态性的Arg16等位基因会增加重症嗜酸粒细胞性哮喘的风险，并可能降低美泊利珠单抗的长期疗效；而Gly16等位基因似乎预示着更好的治疗结局和更高的临床缓解率。
（中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校）
（Allergy 2025 Sep 23;(0);DOI:10.1111/all.70071.IF: 8.706）
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
Santi, Nolasco; Evelina, Fagone; Raffaele,
Abstrast
BACKGROUND: β(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 β(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 FEV(1) decline ≤ 5% from baseline.
CONCLUSION: 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.
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