Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Department of Cardiology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA.
J Pediatr. 2020 Jul;222:213-220.e5. doi: 10.1016/j.jpeds.2020.03.064.
To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial.
In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models.
Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status.
In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
通过对大型随机试验数据进行分析，检验 ADRB1 和 CYP2C9 基因变异是否可以识别对马凡综合征治疗反应不同的个体亚组。
在之前一项关于阿替洛尔与氯沙坦治疗马凡综合征的随机试验的一个子集中，对 250 名白种非西班牙裔马凡综合征患者的常见变异 rs1801252 和 rs1801253 在 ADRB1 以及 rs1799853 和 rs1057910 在 CYP2C9 进行分析。主要结果是通过混合效应模型评估 3 年内最大主动脉根部直径 z 分数的基线调整后的年变化率。
在 122 名接受阿替洛尔治疗的患者中，rs1801253 CC 基因型的 70 名患者主动脉根部 z 分数的改善速度快于 52 名 CG 或 GG 基因型的患者（时间与基因型交互作用 P=0.005，平均每年 z 分数变化±标准误-0.20±0.03 与-0.09±0.03）。在两个治疗组均为 CC 基因型的患者中，与接受氯沙坦治疗的 121 名患者中的 71 名相比，接受阿替洛尔治疗的患者改善速度更快（交互作用 P=0.002；-0.20±0.02 与-0.07±0.02；P<0.001）。阿替洛尔反应不受 rs1801252 基因型的影响，氯沙坦反应不受 CYP2C9 代谢物状态的影响。
在这项探索性研究中，ADRB1-rs1801253 与马凡综合征儿童和青年的阿替洛尔反应相关。如果这些发现得到未来研究的证实，那么 ADRB1 基因分型有可能通过识别那些对阿替洛尔治疗反应比氯沙坦更好的患者来指导治疗。
