Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema.

Pare G, Kubo M, Byrd JB, McCarty CA, Woodard-Grice A, Teo KK, Anand SS, Zuvich RL, Bradford Y, Ross S, Nakamura Y, Ritchie M, Brown NJ
Pharmacogenet Genomics. 2013 23 (9): 470-8

PMID: 23838604 · PMCID: PMC3904664 · DOI:10.1097/FPC.0b013e328363c137

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.

MeSH Terms (19)

African Americans Angioedema Angiotensin-Converting Enzyme Inhibitors Benzimidazoles Benzoates Double-Blind Method Drug Therapy, Combination European Continental Ancestry Group Genome-Wide Association Study Humans Isoenzymes Neprilysin Polymorphism, Single Nucleotide Protein Kinase C Protein Kinase C-theta Proto-Oncogene Proteins c-ets Ramipril Repressor Proteins Telmisartan

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