A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population.

Jacquiline Wangui Mugo, Cascia Day, Ananyo Choudhury, Maria Deetlefs, Robert Freercks, Sian Geraty, Angelica Panieri, Christian Cotchbos, Melissa Ribeiro, Adelein Engelbrecht, Lisa K. Micklesfield, Michèle Ramsay, Sarah Pedretti, Jonny Peter
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Abstract

Background: Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population. Methods: The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls). Results: No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10-06). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs. Conclusions: Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.
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南非人群中 ACE 抑制剂诱发血管性水肿的基因组研究。
背景:血管紧张素转换酶抑制剂诱发的血管性水肿(AE-ACEI)是一种危及生命的不良事件,也是全球血管性水肿急诊中最常见的病因。几项大型全基因组关联研究(GWAS)发现了 AE-ACEI 的基因组关联。然而,尽管非裔美国人患 AE-ACEI 的风险增加了 5 倍,但目前还没有发表过非洲的 GWAS。本研究的目的是在南非人群中开展 AE-ACEI 的病例对照基因组研究,并与非裔美国人和欧洲裔美国人进行荟萃分析:GWAS包括202名有AE-ACE病史的南非成年人和513名接受血管紧张素转换酶抑制剂(ACEI)治疗至少2年后无血管性水肿的对照者。利用非裔美国人和欧洲裔美国人队列(来自 Vanderbilt/Marshfield 的 174 例病例和 489 例对照)的 GWAS 统计摘要进行了荟萃分析。分析结果没有 SNPs 具有全基因组意义。然而,南非队列输入后标准 GWAS 中的 26 个 SNPs 和荟萃分析中的 37 个 SNPs 与 AE-ACEI 相关,具有提示性阈值(p-value<5.0×10-06)。其中一些SNPs被发现位于PRKCQ和RIMS1基因附近,这两个基因以前曾与药物诱发的血管性水肿有关,而且也靠近与ACEI咳嗽有关的CSMD1基因,这提供了基因水平上的复制,但有新的先导SNPs:我们的研究结果凸显了非洲人群在复制研究中检测新型变异体的重要性。需要在非洲大陆进一步增加采样并开展匹配的功能性工作,以确认基因变异在了解 AE-ACEI 生物学方面的重要性。
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