title: [Combination of DAT and DBH gene polymorphisms with a family history of alcohol use disorders increases the risk of withdrawal seizures and delirium tremens during alcohol withdrawal in alcohol-dependent men].
abstract: OBJECTIVE
  To explore the genetic influence of a family history of alcohol use disorders and the dopamine transporter SLC6A3 (DAT1) and dopamine beta-hydroxylase (DBH) gene polymorphisms on the risk of severe complications (withdrawal seizures (AWS) and delirium tremens (DT)) during alcohol withdrawal in alcohol-dependent men.
  
  
  METHODS
  We investigated the effects of 3 previously reported candidate genetic variations: 40-bp variable number tandem repeat (VNTR) polymorphism and C/T exon 15 (rs27072) in the 3' untranslated region (3' UTR) of the SLC6A3(DAT1) gene, and -1021 C/T (rs1611115) of DBH gene in 266 alcohol-dependent Russian male inpatients in two groups by presence (SC group: AWS, DT, AWS+DT, n=130) or absence (n=136) of severe complications diagnosed by ICD-10 during current alcohol withdrawal. Clinically important information and a family history of alcohol use disorders (FH) were obtained by semi-structured interview.
  
  
  RESULTS
  Patients in SC group more often have positive FH (54.6% vs. 33%, p=0.001) and their age at first alcohol use (FAU) was lower (16±3.53y.o vs. 17±1.66 y.o, p=0.001). Logistic regression revealed that FH predicts severe complications in total (р=0.001) and DT (р=0.003), FAU independently predicts severe complications in total (р=0.008), AWS (р=0.04), DT (р=0.032), AWS+DT (р=0.048) and every year of delay alcohol use decreases the risk by 18-30%. The gene polymorphisms interact with FAU to decrease the FAU influence on the risk of AWS (T variant of DAT (rs27072), р=0.04), (AWS+DT) and DT (T variant of DBH (rs1611115), р=0.023 and р=0.06). The T variant of DAT (rs27072) is associated with FAU (p=0.007) and increases the risk of (AWS+DT) (р=0.036), but decreases the risk of AWS (р=0.038) and of DT (р=0.021) too, but only in interaction with positive FH. The 9 repeat variant (9R) of DAT VNTR is associated with AWS (p=0.009), but the risk of AWS (р=0.004) and of SC in total (р=0.001) are elevated only in 9R carriers with positive FH. The 9R independently increases the risk of DT (р=0.048) and the effect become more robust in 9R carriers with high density of FH (р=0.014). The gene x gene interaction decreases the risk of DT (р=0.055). According to an analysis of total cohort of patients, the T variant of DBH (rs1611115) is associated with any kind of manifestation of delirium in alcohol-dependent men (p=0.039).
  
  
  CONCLUSIONS
  This study demonstrate the genetic influence of a family history of alcohol use disorders and DAT and DBH gene polymorphisms on the risk of withdrawal seizures and delirium tremens. The interaction of genetic variations with positive family history provides the most robust effect, the interaction of genetic variations with the age at first alcohol use may «protect» their carriers from negative influence of this «behavioral» risk factor. Replication in large cohorts of patients is necessary to verify these findings for subsequent use in prevention programs.
authors.affiliation: Serbsky Federal Medical Research Center of Psychiatry and Narcology, Ministry of Health, Moscow, Russia.
authors.forename: A O
authors.initials: AO
authors.lastname: Kibitov
authors.affiliation: Russian Medical Academy of Postgraduate Education, Moscow, Russia; Moscow Research Center of Narcology, Moscow, Russia.
authors.forename: D V
authors.initials: DV
authors.lastname: Ivashchenko
authors.affiliation: Serbsky Federal Medical Research Center of Psychiatry and Narcology, Ministry of Health, Moscow, Russia.
authors.forename: V M
authors.initials: VM
authors.lastname: Brodyansky
authors.affiliation: Serbsky Federal Medical Research Center of Psychiatry and Narcology, Ministry of Health, Moscow, Russia.
authors.forename: N A
authors.initials: NA
authors.lastname: Chuprova
authors.affiliation: Shchelkovo Region Dispensary of Narcology, Shchelkovo, Moscow Region, Russia.
authors.forename: S A
authors.initials: SA
authors.lastname: Shuvalov
mesh_terms: D000328:Adult; D000368:Aged; D000430:Alcohol Withdrawal Delirium / Q000453:epidemiology*; D020270:Alcohol Withdrawal Seizures / Q000453:epidemiology*; D000437:Alcoholism / Q000453:epidemiology* / Q000235:genetics*; D000483:Alleles; D015331:Cohort Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D004843:Epistasis, Genetic; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012426:Russia / Q000453:epidemiology; D055815:Young Adult
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D004299:Dopamine beta-Hydroxylase