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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)470-478
Number of pages9
JournalPharmacogenetics and Genomics
Volume23
Issue number9
DOIs
Publication statusPublished - 01-09-2013

Fingerprint

Angioedema
Angiotensin-Converting Enzyme Inhibitors
Ramipril
Single Nucleotide Polymorphism
African Americans
Alleles
Neprilysin
Genome-Wide Association Study
Genetic Association Studies
Bradykinin
Substance P
Genes
Genome
telmisartan
Enzymes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Pare, Guillaume ; Kubo, Michiaki ; Byrd, James B. ; McCarty, Catherine A. ; Woodard-Grice, Alencia ; Teo, Koon K. ; Anand, Sonia S. ; Zuvich, Rebecca L. ; Bradford, Yuki ; Ross, Stephanie ; Nakamura, Yusuke ; Ritchie, Marylyn ; Brown, Nancy J. / Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. In: Pharmacogenetics and Genomics. 2013 ; Vol. 23, No. 9. pp. 470-478.
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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.",
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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 2013, 'Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema', Pharmacogenetics and Genomics, vol. 23, no. 9, pp. 470-478. https://doi.org/10.1097/FPC.0b013e328363c137

Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. / Pare, Guillaume; Kubo, Michiaki; Byrd, James B.; McCarty, Catherine A.; Woodard-Grice, Alencia; Teo, Koon K.; Anand, Sonia S.; Zuvich, Rebecca L.; Bradford, Yuki; Ross, Stephanie; Nakamura, Yusuke; Ritchie, Marylyn; Brown, Nancy J.

In: Pharmacogenetics and Genomics, Vol. 23, No. 9, 01.09.2013, p. 470-478.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema

AU - Pare, Guillaume

AU - Kubo, Michiaki

AU - Byrd, James B.

AU - McCarty, Catherine A.

AU - Woodard-Grice, Alencia

AU - Teo, Koon K.

AU - Anand, Sonia S.

AU - Zuvich, Rebecca L.

AU - Bradford, Yuki

AU - Ross, Stephanie

AU - Nakamura, Yusuke

AU - Ritchie, Marylyn

AU - Brown, Nancy J.

PY - 2013/9/1

Y1 - 2013/9/1

N2 - 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.

AB - 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.

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