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Randomized Controlled Trial
. 2013 Sep;23(9):470-8.
doi: 10.1097/FPC.0b013e328363c137.

Genetic Variants Associated With Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema

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Free PMC article
Randomized Controlled Trial

Genetic Variants Associated With Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema

Guillaume Pare et al. Pharmacogenet Genomics. .
Free PMC article

Abstract

Objective: The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.

Participants and methods: 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).

Results: 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.

Conclusion: 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.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

Fig. 1
Fig. 1
(a) The results of tests for a trend in the association between angiotensin-converting enzyme (ACE) inhibitor-associated angioedema and each single-nucleotide polymorphism (SNP) measured in the GWAS in participants Nashville/Marshfield study (irrespective of ethnicity). The analysis was adjusted for age and sex. Rs2724635 and Rs500766, indicated in green, were associated with ACE inhibitor-associated angioedema in ONTARGET. (b) The results of tests for a trend in the association between ACE inhibitor-associated angioedema and each SNP measured in the GWAS in African Americans from the Nashville/Marshfield study. The analysis was adjusted for age and sex. Rs2724635, indicated in green, was associated with ACE inhibitor-associated angioedema in ONTARGET. (c) The results of tests for a trend in the association between ACE inhibitor-associated angioedema and each SNP measured in the GWAS in European Americans from the Nashville/Marshfield study. The analysis was adjusted for age and sex. Rs500766, indicated in green, was associated with ACE inhibitor-associated angioedema in ONTARGET.

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