title: Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT(3) antagonist ondansetron.
abstract: OBJECTIVE
  The authors previously reported that the 5'-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, they explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron.
  
  
  METHODS
  The authors genotyped one rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that they genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 mg/kg of body weight twice daily) or placebo along with weekly cognitive-behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed.
  
  
  RESULTS
  Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (22.50; effect size=0.867), percentage of heavy drinking days (220.58%; effect size=0.780), and percentage of days abstinent (18.18%; effect size=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in the previous study) to 34%.
  
  
  CONCLUSIONS
  The authors present initial evidence suggesting that a combined fivemarker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate these results.
authors.forename: Bankole A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Chamindi
authors.initials: C
authors.lastname: Seneviratne
authors.forename: Xin-Qun
authors.initials: XQ
authors.lastname: Wang
authors.forename: Nassima
authors.initials: N
authors.lastname: Ait-Daoud
authors.forename: Ming D
authors.initials: MD
authors.lastname: Li
mesh_terms: D000328:Adult; D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics; D015928:Cognitive Behavioral Therapy; D003131:Combined Modality Therapy; D016903:Drug Monitoring; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D017294:Ondansetron / Q000008:administration & dosage / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; C509409:HTR3A protein, human; C509410:HTR3B protein, human; D044406:Receptors, Serotonin, 5-HT3; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017294:Ondansetron
references.citation: Hum Genet. 2013 Oct;132(10):1165-76
references.pmid: 23757001
references.citation: Mol Cell Neurosci. 2002 Sep;21(1):38-50
references.pmid: 12359150
references.citation: Nat Rev Genet. 2009 Jun;10(6):392-404
references.pmid: 19434077
references.citation: Front Biosci. 2002 May 01;7:a80-9
references.pmid: 11991856
references.citation: Bioorg Med Chem Lett. 2004 Apr 19;14(8):1849-53
references.pmid: 15050614
references.citation: Am J Hum Genet. 2009 Sep;85(3):309-20
references.pmid: 19733727
references.citation: Biol Psychiatry. 2000 Apr 1;47(7):643-9
references.pmid: 10745057
references.citation: Biol Psychiatry. 2007 Apr 1;61(7):911-22
references.pmid: 17217930
references.citation: Am J Psychiatry. 2011 Mar;168(3):265-75
references.pmid: 21247998
references.citation: Alcohol Clin Exp Res. 2004 Feb;28(2):257-67
references.pmid: 15112933
references.citation: Psychiatry Res. 2000 Sep 25;96(1):51-61
references.pmid: 10980326
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):209-16
references.pmid: 17950969
references.citation: Eur J Hum Genet. 2008 Sep;16(9):1075-82
references.pmid: 18382477
references.citation: Am J Hum Genet. 2008 Sep;83(3):311-21
references.pmid: 18691683
references.citation: Genet Epidemiol. 2011;35 Suppl 1:S12-7
references.pmid: 22128052
references.citation: Pharmacogenet Genomics. 2010 Apr;20(4):274-6
references.pmid: 20168265
references.citation: Alcohol Clin Exp Res. 2003 May;27(5):812-7
references.pmid: 12766626
references.citation: Annu Rev Genet. 2010;44:293-308
references.pmid: 21047260
references.citation: Mol Psychiatry. 2011 Nov;16(11):1139-46
references.pmid: 20838391
references.citation: Am J Med Genet. 2002 Aug 8;114(6):593-7
references.pmid: 12210271
references.citation: Neuropharmacology. 2000 Jan 4;39(2):308-15
references.pmid: 10670426
references.citation: Alcohol Clin Exp Res. 2009 Feb;33(2):332-9
references.pmid: 19032574
references.citation: Biochem Pharmacol. 2008 Jan 1;75(1):34-56
references.pmid: 17880925
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):722-7
references.pmid: 18184810
references.citation: PLoS One. 2009 Sep 18;4(9):e7055
references.pmid: 19763258
references.citation: Nat Rev Genet. 2010 Nov;11(11):773-85
references.pmid: 20940738
references.citation: Am J Hum Genet. 2007 Jun;80(6):1125-37
references.pmid: 17503330
references.citation: PLoS Genet. 2009 Feb;5(2):e1000384
references.pmid: 19214210
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: J Stud Alcohol. 1995 Jul;56(4):423-32
references.pmid: 7674678
references.citation: J Biol Chem. 1999 Oct 22;274(43):30799-810
references.pmid: 10521471
references.citation: Neuropsychopharmacology. 2004 Oct;29(10):1807-13
references.pmid: 15162158
references.citation: Ann Biomed Eng. 2008 Jun;36(6):877-88
references.pmid: 18330705
references.citation: Alcohol Clin Exp Res. 2010 Dec;34(12):2022-34
references.pmid: 20659066
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: J Neural Transm (Vienna). 2003 May;110(5):561-72
references.pmid: 12721816
references.citation: Cell Immunol. 2009;255(1-2):1-7
references.pmid: 18834972
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2004 Apr 1;126B(1):124-7
references.pmid: 15048662
references.citation: Mol Pharmacol. 2007 Jul;72(1):8-17
references.pmid: 17392525
references.citation: Biol Psychiatry. 2008 Dec 1;64(11):951-7
references.pmid: 18534558
references.citation: Alcohol. 2009 Feb;43(1):73-84
references.pmid: 19185213
references.citation: Alcohol Clin Exp Res. 2003 Feb;27(2):169-76
references.pmid: 12605066