Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
复制标题
DOI：
10.1038/s41397-020-0165-2
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Wadelius M
中科院分区：
文献类型：
--
作者：
Rasmussen ER;Hallberg P;Baranova EV;Eriksson N;Karawajczyk M;Johansson C;Cavalli M;Maroteau C;Veluchamy A;Islander G;Hugosson S;Terreehorst I;Asselbergs FW;Norling P;Johansson HE;Kohnke H;Syvänen AC;Siddiqui MK;Lang CC;Magnusson PKE;Yue QY;Wadelius C;von Buchwald C;Bygum A;Alfirevic A;Maitland-van der Zee AH;Palmer CNA;Wadelius M
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）治疗的一种令人担忧的不良反应，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鉴定易患这些药物诱导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例对照。在候选基因分析中，ETV 6、BDKRB 2、MME和PRKCQ名义上与血管性水肿相关（p < 0.05），但没有通过多重检验的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（KCNMA 1）基因的内含子变异与血管性水肿显著相关（p < 5 × 10−8）。虽然在复制队列中，KCNMA 1的最高命中率并不显著，（来自美国和北方的413例病例和599例ACEi暴露对照），对复制和发现队列的荟萃分析（共586例病例和1944例ACEi暴露对照）显示，每个变异等位基因使发生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KCNMA 1变异体是不知道的功能，但在连锁不平衡与相关组织中的转录因子结合位点活性的变体。总之，我们的数据表明，KCNMA 1的常见变异与ACEi或ARB治疗诱导的血管性水肿风险相关。未来的全外显子组或基因组测序研究将显示KCNMA 1或其他基因的罕见变异是否会导致ACEi和ARB诱导的血管性水肿的风险。
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.
登录
查看更多内容
影响因子：
14.9
作者：
Kheradpour P;Kellis M
通讯作者：
Kellis M
影响因子：
2.7
作者：
Levy, Jonathan;Rivard, Georges-Etienne;Sussman, Gordon L.
通讯作者：
Sussman, Gordon L.
影响因子：
37.8
作者：
Campbell, DJ;Krum, H;Esler, MD
通讯作者：
Esler, MD
影响因子：
3.4
作者：
Lawlor, Claire M.;Ananth, Ashwin;McCoul, Edward D.
通讯作者：
McCoul, Edward D.
影响因子：
9.8
作者：
Duan, QL;Nikpoor, B;Rouleau, GA
通讯作者：
Rouleau, GA