From the Cardiovascular Division, Department of Medicine, Brigham and
Women's Hospital (R.Y.L.Z., V.S.R., K.L.), and the Department of
Cardiology, Children's Hospital, Harvard Medical School (K.L.), Boston,
Mass; the Dean Medical Center, Oregon, Wisc (R.Z.P.); the Merck Research
Laboratories, West Point, Pa (C.S.S.); the Max Delbruck Centre for Molecular
Medicine, Berlin, Germany (K.L.); and the Cardiovascular Discovery Unit, F.
Hoffmann-La Roche Ltd, Basel, Switzerland (K.L.).
Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail kl{at}calvin.bwh.harvard.edu
Abstract—Unexplained, persistent
cough limits the use of angiotensin-converting enzyme (ACE)
inhibitors in a significant number of patients. It has been
speculated that occurrence of this adverse effect is genetically
predetermined; in particular, variants of the genes encoding ACE,
chymase, and B2-bradykinin receptor have been implicated. To
investigate this question, we determined genotypes for common
polymorphisms for these three genes in subjects with a history of
ACE inhibitor–related cough. Specificity of the adverse
effect was confirmed by a blinded, double-crossover design protocol in
which subjects were rechallenged with either lisinopril or
placebo. In 99 case subjects and 70 control subjects (who failed to
develop cough on rechallenge with ACE inhibitor) thus
selected, frequencies for the ACE D and I
alleles were 0.56 and 0.44 (cases) and 0.56 and 0.44 (controls),
respectively; frequencies for chymase A and
B alleles (absence/presence of BstXI
site) were 0.56 and 0.44 (cases) and 0.46 and 0.54 (controls),
respectively; frequencies for B2-bradykinin receptor +
and - alleles (presence/absence of a 21 to 29
nonanucleotide sequence) were 0.52 and 0.48 (cases) and
0.53 and 0.47 (controls), respectively. All observed genotype
frequencies were in Hardy-Weinberg equilibrium. There was no evidence
for association between genotype at either gene examined and
cough (adjusted for gender and age). Our data indicate that common
genetic variants of ACE, chymase, and B2-bradykinin receptor do not
explain the occurrence of ACE inhibitor–related cough.
© 1998 American Heart Association, Inc.
Scientific Contributions
Three Candidate Genes and Angiotensin-Converting Enzyme Inhibitor–Related Cough
A Pharmacogenetic Analysis
Key Words: angiotensin-converting enzyme inhibitors • cough • angiotensin-converting enzyme • chymase • receptors, bradykinin • polymorphism • genetics
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