Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.
Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.
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DOI：
10.1002/cpt.1927
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发表时间：
2020-12
影响因子：
6.7
通讯作者：
Palmer, Colin N. A.
中科院分区：
文献类型：
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作者：
Maroteau, Cyrielle;Siddiqui, Moneeza Kalhan;Veluchamy, Abirami;Carr, Fiona;White, Myra;Cassidy, Andrew J.;Baranova, Ekaterina, V;Rasmussen, Eva R.;Eriksson, Niclas;Bloch, Katarzyna M.;Brown, Nancy J.;Bygum, Anette;Hallberg, Par;Karawajczyk, Malgorzata;Magnusson, Patrik K. E.;Yue, QunYing;Syvnen, AnnChristine;Buchwald, Christian;Alfirevic, Ana;Maitland-van der Zee, Anke H.;Wadelius, Mia;Palmer, Colin N. A.
发生在头颈部的血管性水肿是血管紧张素转换酶抑制剂（ACEIs）和血管紧张素受体阻滞剂（ARB）的一种罕见且有时危及生命的不良反应。很少有研究调查常见变异与这种极端反应的关联，但还没有研究过罕见变异的综合影响。在5个不同的研究中心招募裁定的ACEI诱导的血管性水肿（ACEI-AE）或ARB诱导的血管性水肿（ARB-AE）病例和对照。使用外显子组富集序列数据对1，066份样本（408份ACEI-AE、ARB-AE和658份对照）进行测序。F5基因的一种常见变异导致凝血增加（rs6025，p.Arg506Gln，也称为因子V Leiden），与ACEI-AE和ARB-AE显著相关（比值比：2.85，95%置信区间（CI），1.89-4.25）。F5中5种罕见错义变异的负荷检验分析也发现与ACEI-AE或ARB-AE相关，P = 2.09 × 10−3。这些变异体以及常见变异体rs6025和rs6020的联合基因风险评分显示，携带至少一种变异体的个体发生ACEI-AE或ARB-AE的几率是其他个体的2.21倍（95% CI，1.49-3.27，P = 6.30 × 10−9）。在美国的一项全基因组关联研究中证实了常见莱顿等位基因导致的风险增加。rs6020变异体也观察到血管性水肿的高风险，该变异体是非洲黑人和亚洲人群中主要的凝血缺陷引起变异体。我们发现F5中有害的错义变异与ACEI-AE或ARB-AE的风险增加相关。
Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10−3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.
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DOI：
10.1038/s41397-020-0165-2
发表时间：
2020-12
期刊：
The pharmacogenomics journal
影响因子：
--
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
通讯作者：
Wadelius M
影响因子：
9.8
作者：
Li, Bingshan;Leal, Suzanne M.
通讯作者：
Leal, Suzanne M.
影响因子：
3
作者：
Mägi R;Morris AP
通讯作者：
Morris AP
影响因子：
9.8
作者：
Duan, QL;Nikpoor, B;Rouleau, GA
通讯作者：
Rouleau, GA
影响因子：
2.6
作者：
Byrd, James Brian;Adam, Albert;Brown, Nancy J.
通讯作者：
Brown, Nancy J.