Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Pharmacogenet Genomics. 2013 Sep;23(9):470-8. doi: 10.1097/FPC.0b013e328363c137.
The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.
We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).
There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans.
Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.
本研究旨在鉴定与血管紧张素转换酶（ACE）抑制剂相关性血管性水肿相关的遗传变异。
我们对 175 名 ACE 抑制剂相关性血管性水肿患者和来自纳什维尔（田纳西州）和马什菲尔德（威斯康星州）的 489 名 ACE 抑制剂暴露对照者进行了全基因组关联研究。我们在 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial（ONTARGET）中对 19 例和 57 例参与者进行了复制检验。
没有任何单核苷酸多态性（SNP）与血管性水肿具有全基因组显著关联。在非洲裔美国人群中，有 16 个 SNP，在欧洲裔美国人群中，有 41 个 SNP 与血管性水肿中度相关（P<10），并在 ONTARGET 中进行了关联评估。PRKCQ 中的 rs500766 的 T 等位基因与 ACE 抑制剂相关性血管性水肿的风险降低相关，而 ETV6 中的 rs2724635 的 G 等位基因与纳什维尔/马什菲尔德样本和 ONTARGET 中 ACE 抑制剂相关性血管性水肿的风险增加相关。在候选基因分析中，编码降解缓激肽和 P 物质的酶——内肽酶 Neprilysin（MME）的基因中的 rs989692 与 ONTARGET 和纳什维尔/马什菲尔德非洲裔美国人的血管性水肿显著相关。
与其他严重药物不良反应不同，ACE 抑制剂相关性血管性水肿与变异的大效应大小无关。MME 中的变异和参与免疫调节的基因可能与 ACE 抑制剂相关性血管性水肿相关。
