Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough
Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough
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DOI：
10.1101/2022.06.30.22277097
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发表时间：
2022-06
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影响因子：
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通讯作者：
Kayesha Coley;David J. Shepherd;R. Packer;C. John;R. Free;J. Edward;Hollox;L. Wain;M. Tobin;C. Batini
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文献类型：
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作者：
Kayesha Coley;David J. Shepherd;R. Packer;C. John;R. Free;J. Edward;Hollox;L. Wain;M. Tobin;C. Batini
血管紧张素转换酶抑制剂(ACEI)通常用于治疗高血压，高血压是心血管疾病的全球风险因素。它们的主要副作用是干咳，影响5%-35%的使用者。由于临床指南建议将咳嗽患者改用血管紧张素-II受体阻滞剂，我们已将这种转换作为血管紧张素转换酶抑制剂诱导的咳嗽的替代药物。通过两个阶段的多祖先全基因组关联研究，包括多达7,030个病例和39,921个对照，我们确定了五个独立的全基因组显著关联，涉及六个蛋白质编码基因，包括编码神经系统相关蛋白质的INHBC、KCNIP4、NTSR1和PREP。通过遗传相关性和表型相关研究，我们还观察到ACEI诱导咳嗽和慢性干咳之间的基因重叠。根据现有的假说，我们的发现提示ACEI诱导咳嗽的病理机制具有神经学基础，特别是促炎介质在感觉气道敏感性和咳嗽反射调节中的作用，并与慢性干咳具有共同的生物学机制。
ACE inhibitors (ACEIs) are commonly prescribed for hypertension, a global risk factor for cardiovascular disease. Their primary side effect is a dry cough which affects 5-35% of users. As clinical guidelines recommend switching those experiencing cough to an angiotensin-II receptor blocker, we have used this switch as a proxy for ACEI-induced cough. Through a two-stage multi-ancestry genome-wide association study, including up to 7,030 cases and 39,921 controls, we identify five independent genome-wide significant associations implicating six protein-coding genes, including INHBC, KCNIP4, NTSR1 and PREP which encode proteins involved in the nervous system. We also observe genetic overlap between ACEI-induced cough and chronic dry cough through genetic correlation and phenome-wide association studies. In line with existing hypotheses, our findings suggest a neurological basis for the pathology of ACEI-induced cough, particularly the role of proinflammatory mediators in sensory airway sensitivity and cough reflex modulation, and shared biological mechanisms with chronic dry cough.