Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate.
In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.
Kiefer
F
F
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany. falk.kiefer@zi-mannheim.de
Witt
S H
SH
Frank
J
J
Richter
A
A
Treutlein
J
J
Lemenager
T
T
Nöthen
M M
MM
Cichon
S
S
Batra
A
A
Berner
M
M
Wodarz
N
N
Zimmermann
U S
US
Spanagel
R
R
Wiedemann
K
K
Smolka
M N
MN
Heinz
A
A
Rietschel
M
M
Mann
K
K
D000077443:Acamprosate; D000328:Adult; D000427:Alcohol Deterrents / Q000627:therapeutic use*; D000437:Alcoholism / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000438:Alcohols / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D012306:Risk; D013654:Taurine / Q000031:analogs & derivatives* / Q000235:genetics / Q000627:therapeutic use
D000427:Alcohol Deterrents; D000438:Alcohols; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D013654:Taurine; D009320:Atrial Natriuretic Factor; D000077443:Acamprosate