Background

Combination treatments, targeting multiple disease processes, benefit subjects with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, predicting treatment response and exacerbation risk remain challenging.

Objective

To identify genetic associations with AECOPD risk and response to combination therapy (fluticasone furoate, umeclidinium bromide and vilanterol).

Methods

The genetic basis of AECOPD disease was investigated in 19,841 subjects from 23 clinical studies and 2 disease cohorts to identify exacerbation disease targets. AECOPD pharmacogenetic effects were examined in 8439 moderate to severe COPD patients with exacerbation rate, lung function and quality of life endpoints; results were followed up in an additional 2201 subjects.

Results

We did not identify significant associations in the AECOPD disease analysis. In the AECOPD pharmacogenetics analysis, rs56195836 (MAPK8) was significantly associated with moderate to severe exacerbation rate in subjects on fluticasone furoate with baseline blood eosinophils ≥150 cells/μl (P = 1.8 × 10⁻⁸). Post-hoc, one variant was associated with on-treatment moderate to severe exacerbation rate stratifying by exacerbation history. AZU1 rs1962343 was significantly associated in subjects with frequent moderate exacerbation history when treated with fluticasone furoate/vilanterol (P = 1.1 × 10⁻⁸). Neither of these signals was supported in independent follow-up.

Conclusion

Common genetic variants do not play major roles in AECOPD disease nor predict response to triple therapy or its components in moderate to very severe COPD.

中文翻译：

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遗传学在预测慢性阻塞性肺疾病治疗反应和恶化方面的作用有限

背景

针对多种疾病过程的联合治疗可使慢性阻塞性肺疾病（AECOPD）急性加重的受试者受益。然而，预测治疗反应和恶化风险仍然具有挑战性。

客观的

确定与 AECOPD 风险和对联合治疗（糠酸氟替卡松、乌美溴铵和维兰特罗）反应的遗传关联。

方法

在来自 23 项临床研究和 2 个疾病队列的 19,841 名受试者中调查了 AECOPD 疾病的遗传基础，以确定恶化疾病的目标。对 8439 名中度至重度 COPD 患者的 AECOPD 药物遗传学效应进行了检查，包括恶化率、肺功能和生活质量终点；结果在另外 2201 名受试者中进行了随访。

结果

我们没有在 AECOPD 疾病分析中发现显着的关联。在 AECOPD 药物遗传学分析中，rs56195836 ( MAPK8 ) 与糠酸氟替卡松基线血嗜酸性粒细胞≥150 细胞/μl 受试者的中度至重度恶化率显着相关 ( P = 1.8 × 10 ^-8 )。事后，一种变异与治疗中的中度至重度恶化率相关，按恶化史分层。当用糠酸氟替卡松/维兰特罗治疗时， AZU1 rs1962343与频繁中度恶化史的受试者显着相关( P  = 1.1 × 10 ^-8 )。这些信号均未在独立随访中得到支持。

结论

常见的遗传变异在 AECOPD 疾病中不发挥主要作用，也不预测对三联疗法或其成分在中度至极重度 COPD 中的反应。