基于新遗传位点发现的 ACE 抑制剂相关性咳嗽多基因风险评分。

Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci.

机构信息

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Building 9312, Henrik Harpestrengs Vej 4C, 2100 Copenhagen, Denmark.

Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

出版信息

Eur Heart J. 2022 Dec 1;43(45):4707-4718. doi: 10.1093/eurheartj/ehac322.

DOI:10.1093/eurheartj/ehac322

PMID:35751511

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10148738/

Abstract

AIMS

To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs).

METHODS AND RESULTS

A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits.

CONCLUSION

This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

摘要

目的

寻找与 ACEi 停药相关的序列变异，并检验其与 ACEi 相关不良反应（ADR）的相关性。

方法和结果

进行了一项 ACEi 停药的全基因组关联研究（GWAS），共纳入 33959 名 ACEi 停药患者和 44041 名对照者。病例定义为从 ACEi 治疗转换为血管紧张素受体阻滞剂治疗的患者。对照者定义为至少继续 ACEi 治疗 1 年的患者。采用混合模型回归分析计算 ACEi 停药风险的比值比（OR）和 95%置信区间（95%CI）。采用固定效应模型对个体队列的汇总统计数据进行荟萃分析。为了检验与特定 ACEi 相关 ADR 的相关性，对任何全基因组显著（P＜5×10-8）的 ACEi 停药变异进行了 ACEi 相关咳嗽和血管性水肿的相关性检验。基于 ACEi 停药 GWAS 数据构建了多基因风险评分（PRS），并在两个基于人群的样本中检验了其与 ACEi 相关咳嗽和血管性水肿的相关性。共确定了 7 个遗传全基因组位点，其中 6 个是以前未报道过的。与 ACEi 停药相关性最强的是 20q13.3（NTSR1；OR：1.21；95%CI：1.17-1.24；P=2.1×10-34）。7 个主要变异中有 5 个与 ACEi 相关咳嗽相关，而与 ACEi 相关血管性水肿均无关。ACEi 停药 PRS 与 ACEi 相关咳嗽呈剂量反应关系，但与 ACEi 相关血管性水肿无关。ACEi 停药与包括胃食管反流病、过敏性鼻炎、花粉症和哮喘在内的重要咳嗽病因在遗传上相关，这表明这些特征之间存在部分共同的遗传基础。