title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pare
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: James B
authors.initials: JB
authors.lastname: Byrd
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.forename: Alencia
authors.initials: A
authors.lastname: Woodard-Grice
authors.forename: Koon K
authors.initials: KK
authors.lastname: Teo
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Zuvich
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ross
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Marylyn
authors.initials: M
authors.lastname: Ritchie
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D001741:Black or African American / Q000235:genetics; D000799:Angioedema / Q000139:chemically induced* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D055106:Genome-Wide Association Study; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D015260:Neprilysin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000235:genetics*; D000074121:Protein Kinase C-theta; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D017257:Ramipril / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D012097:Repressor Proteins / Q000235:genetics*; D000077333:Telmisartan; D044465:White People / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D007527:Isoenzymes; D015260:Neprilysin; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D050783:Proto-Oncogene Proteins c-ets; D017257:Ramipril; D012097:Repressor Proteins; D000077333:Telmisartan; D000097764:ETS Translocation Variant 6 Protein; C076233:PRKCQ protein, human; C436550:MMEL1 protein, human