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

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.

• Authors: Guillaume Pare, Michiaki Kubo, James B Byrd, Catherine A McCarty, Alencia Woodard-Grice, Koon K Teo, Sonia S Anand, Rebecca L Zuvich, Yuki Bradford, Stephanie Ross, Yusuke Nakamura, Marylyn Ritchie, Nancy J Brown
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 23 Issue 9 Pg. 470-8 (Sep 2013) ISSN: 1744-6880 [Electronic] United States
• PMID: 23838604 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Benzimidazoles
• Benzoates
• ETS translocation variant 6 protein
• Isoenzymes
• Proto-Oncogene Proteins c-ets
• Repressor Proteins
• PRKCQ protein, human
• Protein Kinase C
• Protein Kinase C-theta
• MMEL1 protein, human
• Neprilysin
• Ramipril
• Telmisartan

Topics

• Black or African American (genetics)
• Angioedema (chemically induced, enzymology, ethnology, genetics)
• Angiotensin-Converting Enzyme Inhibitors (adverse effects, metabolism)
• Benzimidazoles (administration & dosage, adverse effects, therapeutic use)
• Benzoates (administration & dosage, adverse effects, therapeutic use)
• Double-Blind Method
• Drug Therapy, Combination
• Genome-Wide Association Study
• Humans
• Isoenzymes (genetics)
• Neprilysin (genetics)
• Polymorphism, Single Nucleotide
• Protein Kinase C (genetics)
• Protein Kinase C-theta
• Proto-Oncogene Proteins c-ets (genetics)
• Ramipril (administration & dosage, adverse effects, therapeutic use)
• Repressor Proteins (genetics)
• Telmisartan
• White People (genetics)