Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.,The Pharmacogenomics Journal

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Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
The Pharmacogenomics Journal ( IF 2.9 ) Pub Date : 2020-02-21 , DOI: 10.1038/s41397-020-0165-2
Eva Rye Rasmussen _{1,

2} , Pär Hallberg ₃ , Ekaterina V Baranova ₄ , Niclas Eriksson _{3,

5} , Malgorzata Karawajczyk ₆ , Caroline Johansson _{3,

7} , Marco Cavalli ₈ , Cyrielle Maroteau ₉ , Abirami Veluchamy ₉ , Gunilla Islander ₁₀ , Svante Hugosson ₁₁ , Ingrid Terreehorst ₁₂ , Folkert W Asselbergs _{13,

14,

15} , Pia Norling ₁₆ , Hans-Erik Johansson ₁₇ , Hugo Kohnke ₃ , Ann-Christine Syvänen ₁₈ , Moneeza K Siddiqui ₉ , Chim C Lang ₁₉ , Patrik K E Magnusson ₂₀ , Qun-Ying Yue ₂₁ , Claes Wadelius ₈ , Christian von Buchwald ₁ , Anette Bygum _{22,

23} , Ana Alfirevic ₂₄ , Anke H Maitland-van der Zee _{4,

25} , Colin N A Palmer ₉ , Mia Wadelius ₃

Affiliation

Department of Otorhinolaryngology, Head & Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
OPEN Patient data Explorative Network, Odense University Hospital, Odense, Denmark.
Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
Uppsala Clinical Research Center, Uppsala, Sweden.
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
Q-Linea AB, Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Medical Genetics and Genomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Division of Population Health and Genomics, University of Dundee, Ninewells Hospital and Medical school, Dundee, UK.
Department of Intensive and Perioperative Care, Skåne University Hospital, Lund, Sweden.
Department of Otorhinolaryngology, Örebro University Hospital and Örebro University, Örebro, Sweden.
Department of Ear, Nose and Throat diseases, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
Health Data Research UK and Institute of Health Informatics, University College London, London, UK.
Sickla Health Centre, Nacka, Sweden.
Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Division of Molecular & Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Uppsala Monitoring Centre, WHO Collaborating Centre, Uppsala, Sweden.
Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark.
Clinical Institute, University of Southern Denmark, Odense, Denmark.
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Department of Respiratory Diseases, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

中文翻译：

血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂治疗引起的血管性水肿的全基因组关联研究。

口腔或上呼吸道血管性水肿是血管紧张素转换酶抑制剂 (ACEi) 和血管紧张素受体阻滞剂 (ARB) 治疗的可怕不良反应，血管紧张素受体阻滞剂用于治疗高血压、心力衰竭和糖尿病并发症。这项候选基因和全基因组关联研究旨在确定易患这些药物引起的血管性水肿的遗传变异。发现队列包括在瑞典招募的 173 例病例和 4890 名对照。在候选基因分析中，ETV6、BDKRB2、MME 和 PRKCQ 名义上与血管性水肿相关（p < 0.05），但未通过多项测试的 Bonferroni 校正（p < 2.89 × 10-5）。在全基因组分析中，10 号染色体上钙激活钾通道亚基 α-1 (KCNMA1) 基因的内含子变异与血管性水肿显着相关（p < 5 × 10-8)。虽然在复制队列（来自美国和北欧的 413 例病例和 599 例暴露于 ACEi 的对照中）最高的 KCNMA1 命中率并不显着，但对复制和发现队列（总共 586 例和 1944 例暴露于 ACEi 的对照）的荟萃分析) 显示，每个变异等位基因将经历血管性水肿的几率增加 1.62 倍（95% 置信区间 1.05-2.50，p = 0.030）。相关的 KCNMA1 变体尚不清楚是否具有功能性，但与相关组织中活跃的转录因子结合位点的变体存在连锁不平衡。总之，我们的数据表明 KCNMA1 的常见变异与 ACEI 或 ARB 治疗引起的血管性水肿风险相关。

更新日期：2020-02-21

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