α-Adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: Results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES)

Tobias Gerhard, Yan Gong, Amber L. Beitelshees, Xianyun Mao, Maximilian T. Lobmeyer, Rhonda M. Cooper-DeHoff, Taimour Y. Langaee, Nicholas J. Schork, Mark Shriver, Carl J. Pepine, Julie A. Johnson

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: The α-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. Methods: The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. Results: In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. Conclusions: In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

Original languageEnglish (US)
Pages (from-to)397-404
Number of pages8
JournalAmerican Heart Journal
Volume156
Issue number2
DOIs
StatePublished - Aug 1 2008

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trandolapril
Verapamil
Diuretics
Hispanic Americans
Coronary Artery Disease
Cause of Death
Homozygote
Stroke
Myocardial Infarction
Genotype
adducin
Hypertension

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Gerhard, Tobias ; Gong, Yan ; Beitelshees, Amber L. ; Mao, Xianyun ; Lobmeyer, Maximilian T. ; Cooper-DeHoff, Rhonda M. ; Langaee, Taimour Y. ; Schork, Nicholas J. ; Shriver, Mark ; Pepine, Carl J. ; Johnson, Julie A. / α-Adducin polymorphism associated with increased risk of adverse cardiovascular outcomes : Results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES). In: American Heart Journal. 2008 ; Vol. 156, No. 2. pp. 397-404.
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title = "α-Adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: Results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES)",
abstract = "Background: The α-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. Methods: The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. Results: In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95{\%} CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. Conclusions: In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.",
author = "Tobias Gerhard and Yan Gong and Beitelshees, {Amber L.} and Xianyun Mao and Lobmeyer, {Maximilian T.} and Cooper-DeHoff, {Rhonda M.} and Langaee, {Taimour Y.} and Schork, {Nicholas J.} and Mark Shriver and Pepine, {Carl J.} and Johnson, {Julie A.}",
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α-Adducin polymorphism associated with increased risk of adverse cardiovascular outcomes : Results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES). / Gerhard, Tobias; Gong, Yan; Beitelshees, Amber L.; Mao, Xianyun; Lobmeyer, Maximilian T.; Cooper-DeHoff, Rhonda M.; Langaee, Taimour Y.; Schork, Nicholas J.; Shriver, Mark; Pepine, Carl J.; Johnson, Julie A.

In: American Heart Journal, Vol. 156, No. 2, 01.08.2008, p. 397-404.

Research output: Contribution to journalArticle

TY - JOUR

T1 - α-Adducin polymorphism associated with increased risk of adverse cardiovascular outcomes

T2 - Results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES)

AU - Gerhard, Tobias

AU - Gong, Yan

AU - Beitelshees, Amber L.

AU - Mao, Xianyun

AU - Lobmeyer, Maximilian T.

AU - Cooper-DeHoff, Rhonda M.

AU - Langaee, Taimour Y.

AU - Schork, Nicholas J.

AU - Shriver, Mark

AU - Pepine, Carl J.

AU - Johnson, Julie A.

PY - 2008/8/1

Y1 - 2008/8/1

N2 - Background: The α-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. Methods: The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. Results: In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. Conclusions: In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

AB - Background: The α-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. Methods: The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. Results: In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. Conclusions: In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

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