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Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol Dependence Using the 5-HT3 Antagonist Ondansetron
Bankole A. Johnson, D.Sc., M.D.; Chamindi Seneviratne, M.D.; Xin-Qun Wang, M.S.; Nassima Ait-Daoud, M.D.; Ming D. Li, Ph.D.
Am J Psychiatry 2013;170:1020-1031. doi:10.1176/appi.ajp.2013.12091163
View Author and Article Information

Dr. Johnson has served as a consultant for ADial Pharmaceuticals (for which he also serves as Chairman), D&A Pharma, Eli Lilly, Organon, and Psychological Education Publishing Company. Dr. Li has served as a consultant and board member for ADial Pharmaceuticals. The other authors report no financial relationships with commercial interests.

ClinicalTrials.gov identifier: NCT00382642.

The authors thank the National Institute on Alcohol Abuse and Alcoholism for its support through grants 5 R01 AA010522-17 and 1 R01 AA021163-01 (to Dr. Johnson) and grant 5 R01 AA019720-02 (to Dr. Ait-Daoud); the National Institute on Drug Abuse for its support of Dr. Li through grant 5 R01 DA012844-12; and Robert H. Cormier, Jr., B.A., for his assistance with manuscript preparation.

From the Department of Psychiatry and Neurobehavioral Sciences and the Department of Public Health Sciences, University of Virginia, Charlottesville.

Address correspondence to Dr. Johnson (bankolejohnson@virginia.edu).

Copyright © 2013 by the American Psychiatric Association

Received September 04, 2012; Revised February 07, 2013; Accepted April 08, 2013.

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.

Method  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 µg/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 (−2.50; effect size=0.867), percentage of heavy drinking days (−20.58%; 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 five-marker 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.

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FIGURE 1. SNP Selection Process and Statistical Analysis Workflowa

a SNP=single-nucleotide polymorphism. The primary outcome measure was drinks per drinking day; the secondary outcome measures were percentage of heavy drinking days and percentage of days abstinent.

FIGURE 2. CONSORT Diagram of Alcohol-Dependent Participants in the Post Hoc Analysisa

a 5′-HTTLPR=serotonin-transporter-linked polymorphic region; SNP=single-nucleotide polymorphism.

b The primary outcome measure was drinks per drinking day; the secondary outcome measures were percentage of heavy drinking days and percentage of days abstinent.

FIGURE 3. Linkage Disequilibrium Analysis of all HTR3A and HTR3B SNPs in the Total Cohort and Location of Significantly Associated SNPsa

a SNPs=single-nucleotide polymorphisms. The numerals in the squares of the linkage disequilibrium plot are r2 values; the dotted lines point toward the location of significantly associated SNPs in reference to various splice variants of HTR3A and HTR3B primary mRNA. The numbers next to each splice variant indicate their accession numbers.

FIGURE 4. Comparison of Means for the Three Drinking Outcome Measuresa

a Graphs in the left-hand column are for participants in the ondansetron or placebo group carrying any one or a combination of the HTR3A-rs1150226-AG, HTR3A-rs1176713-GG, and/or HTR3B-rs17614942-AC genotypes (genotype combination 3) who showed the best treatment response and for those not carrying these genotypes (“all others”). Graphs in the right-hand column are for participants in the ondansetron or placebo group carrying any one or a combination of the SLC6A4-LL/TT, HTR3A-rs1150226-AG, HTR3A-rs1176713-GG, and/or HTR3B-rs17614942-AC genotypes (genotype combination 4) and for those not possessing any of these genotypes (“all others”).

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TABLE 1.Significant Individual HTR3A and HTR3B SNP Associations With Three Drinking Measuresa
Table Footer Note

a All comparisons are between the ondansetron and placebo groups. SNP=single-nucleotide polymorphism; EMD=estimated mean difference.

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TABLE 2.Association of Frequent Genotype Combinations (>5%) with Primary and Secondary Outcome Measures of Ondansetron Treatment Responsea
Table Footer Note

a All comparisons are between the ondansetron and placebo groups and are listed in descending order of magnitude of their reductions in drinks per drinking day; mean differences for drinks per drinking day are in standard drinks; negative values indicate improvement from baseline. EMD=estimated mean difference.

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TABLE 3.SNP-by-SNP Interaction Models Detected to Be Significant Using the GMDR Method, With the Closest Resemblance to Combinations 1–4 From the Primary Analysisa
Table Footer Note

a SNP=single-nucleotide polymorphism; GMDR=generalized multifactor dimensionality reduction.

Table Footer Note

b Generated with 106 permutations.

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References

Enoch  M-A;  Schuckit  MA;  Johnson  BA;  Goldman  D:  Genetics of alcoholism using intermediate phenotypes.  Alcohol Clin Exp Res 2003; 27:169–176
[CrossRef] | [PubMed]
 
Johnson  BA:  Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.  Biochem Pharmacol 2008; 75:34–56
[CrossRef] | [PubMed]
 
Johnson  BA;  Ait-Daoud  N;  Seneviratne  C;  Roache  JD;  Javors  MA;  Wang  X-Q;  Liu  L;  Penberthy  JK;  DiClemente  CC;  Li  MD:  Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking.  Am J Psychiatry 2011; 168:265–275
[CrossRef] | [PubMed]
 
McBride  WJ;  Lovinger  DM;  Machu  T;  Thielen  RJ;  Rodd  ZA;  Murphy  JM;  Roache  JD;  Johnson  BA:  Serotonin-3 receptors in the actions of alcohol, alcohol reinforcement, and alcoholism.  Alcohol Clin Exp Res 2004; 28:257–267
[CrossRef] | [PubMed]
 
Niesler  B;  Walstab  J;  Combrink  S;  Möller  D;  Kapeller  J;  Rietdorf  J;  Bönisch  H;  Göthert  M;  Rappold  G;  Brüss  M:  Characterization of the novel human serotonin receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E.  Mol Pharmacol 2007; 72:8–17
[CrossRef] | [PubMed]
 
Papke  RL;  Porter Papke  JK;  Rose  GM:  Activity of alpha7-selective agonists at nicotinic and serotonin 5HT3 receptors expressed in Xenopus oocytes.  Bioorg Med Chem Lett 2004; 14:1849–1853
[CrossRef] | [PubMed]
 
Boyd  GW;  Low  P;  Dunlop  JI;  Robertson  LA;  Vardy  A;  Lambert  JJ;  Peters  JA;  Connolly  CN:  Assembly and cell surface expression of homomeric and heteromeric 5-HT3 receptors: the role of oligomerization and chaperone proteins.  Mol Cell Neurosci 2002; 21:38–50
[CrossRef] | [PubMed]
 
Johnson  BA;  Javors  MA;  Roache  JD;  Seneviratne  C;  Bergeson  SE;  Ait-Daoud  N;  Dawes  MA;  Ma  JZ:  Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking? Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:209–216
[CrossRef] | [PubMed]
 
Barr  CS;  Newman  TK;  Becker  ML;  Champoux  M;  Lesch  KP;  Suomi  SJ;  Goldman  D;  Higley  JD:  Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress.  Alcohol Clin Exp Res 2003; 27:812–817
[CrossRef] | [PubMed]
 
Preuss  UW;  Soyka  M;  Bahlmann  M;  Wenzel  K;  Behrens  S;  de Jonge  S;  Krüger  M;  Bondy  B:  Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), [3H]paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity.  Psychiatry Res 2000; 96:51–61
[CrossRef] | [PubMed]
 
Heinz  A;  Jones  DW;  Mazzanti  C;  Goldman  D;  Ragan  P;  Hommer  D;  Linnoila  M;  Weinberger  DR:  A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity.  Biol Psychiatry 2000; 47:643–649
[CrossRef] | [PubMed]
 
Dubin  AE;  Huvar  R;  D’Andrea  MR;  Pyati  J;  Zhu  JY;  Joy  KC;  Wilson  SJ;  Galindo  JE;  Glass  CA;  Luo  L;  Jackson  MR;  Lovenberg  TW;  Erlander  MG:  The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit.  J Biol Chem 1999; 274:30799–30810
[CrossRef] | [PubMed]
 
Krzywkowski  K;  Davies  PA;  Feinberg-Zadek  PL;  Bräuner-Osborne  H;  Jensen  AA:  High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor.  Proc Natl Acad Sci USA 2008; 105:722–727
[CrossRef] | [PubMed]
 
Hodge  CW;  Kelley  SP;  Bratt  AM;  Iller  K;  Schroeder  JP;  Besheer  J:  5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking.  Neuropsychopharmacology 2004; 29:1807–1813
[CrossRef] | [PubMed]
 
Enoch  MA;  Gorodetsky  E;  Hodgkinson  C;  Roy  A;  Goldman  D:  Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence.  Mol Psychiatry 2011; 16:1139–1146
[CrossRef] | [PubMed]
 
Ducci  F;  Enoch  MA;  Yuan  Q;  Shen  PH;  White  KV;  Hodgkinson  C;  Albaugh  B;  Virkkunen  M;  Goldman  D:  HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power: an intermediate phenotype for alcoholism and co-morbid behaviors.  Alcohol 2009; 43:73–84
[CrossRef] | [PubMed]
 
Bohn  MJ;  Babor  TF;  Kranzler  HR:  The Alcohol Use Disorders Identification Test (AUDIT): validation of a screening instrument for use in medical settings.  J Stud Alcohol 1995; 56:423–432
[PubMed]
 
Kadden  R;  Carroll  K;  Donovan  D;  Cooney  N;  Monti  P;  Abrams  D;  Litt  M;  Hester  R:  Cognitive-Behavioral Coping Skills Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse and Dependence (NIH Publication No 92-1895) .  Washington, DC,  US Department of Health and Human Services, 1992
 
Sobell  LC;  Sobell  MB:  Timeline follow-back: a technique for assessing self-reported alcohol consumption, in  Measuring Alcohol Consumption: Psychosocial and Biochemical Methods . Edited by Litten  RZ;  Allen  JP.  Totowa, NJ,  Humana Press, 1992, pp 41–72
 
Seneviratne  C;  Huang  W;  Ait-Daoud  N;  Li  MD;  Johnson  BA:  Characterization of a functional polymorphism in the 3′ UTR of SLC6A4 and its association with drinking intensity.  Alcohol Clin Exp Res 2009; 33:332–339
[CrossRef] | [PubMed]
 
Barrett  JC;  Fry  B;  Maller  J;  Daly  MJ:  Haploview: analysis and visualization of LD and haplotype maps.  Bioinformatics 2005; 21:263–265
[CrossRef] | [PubMed]
 
Benjamini  Y;  Drai  D;  Elmer  G;  Kafkafi  N;  Golani  I:  Controlling the false discovery rate in behavior genetics research.  Behav Brain Res 2001; 125:279–284
[CrossRef] | [PubMed]
 
Cohen  J:  Statistical Power Analysis for the Behavioral Sciences , 2nd ed.  Hillsdale, NJ,  Lawrence Erlbaum Associates, 1988
 
Lou  XY;  Chen  GB;  Yan  L;  Ma  JZ;  Zhu  J;  Elston  RC;  Li  MD:  A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence.  Am J Hum Genet 2007; 80:1125–1137
[CrossRef] | [PubMed]
 
Cordell  HJ:  Detecting gene-gene interactions that underlie human diseases.  Nat Rev Genet 2009; 10:392–404
[CrossRef] | [PubMed]
 
Moore  JH;  Williams  SM:  Epistasis and its implications for personal genetics.  Am J Hum Genet 2009; 85:309–320
[CrossRef] | [PubMed]
 
Dering  C;  Hemmelmann  C;  Pugh  E;  Ziegler  A:  Statistical analysis of rare sequence variants: an overview of collapsing methods.  Genet Epidemiol 2011; 35(suppl 1):S12–S17
[CrossRef] | [PubMed]
 
Li  B;  Leal  SM:  Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data.  Am J Hum Genet 2008; 83:311–321
[CrossRef] | [PubMed]
 
Asimit  J;  Zeggini  E:  Rare variant association analysis methods for complex traits.  Annu Rev Genet 2010; 44:293–308
[CrossRef] | [PubMed]
 
Bansal  V;  Libiger  O;  Torkamani  A;  Schork  NJ:  Statistical analysis strategies for association studies involving rare variants.  Nat Rev Genet 2010; 11:773–785
[CrossRef] | [PubMed]
 
Madsen  BE;  Browning  SR:  A groupwise association test for rare mutations using a weighted sum statistic.  PLoS Genet 2009; 5:e1000384
[CrossRef] | [PubMed]
 
Li  MD;  Lou  XY;  Chen  G;  Ma  JZ;  Elston  RC:  Gene-gene interactions among CHRNA4, CHRNB2, BDNF, and NTRK2 in nicotine dependence.  Biol Psychiatry 2008; 64:951–957
[CrossRef] | [PubMed]
 
Li  MD;  Mangold  JE;  Seneviratne  C;  Chen  GB;  Ma  JZ;  Lou  XY;  Payne  TJ:  Association and interaction analyses of GABBR1 and GABBR2 with nicotine dependence in European- and African-American populations.  PLoS ONE 2009; 4:e7055
[CrossRef] | [PubMed]
 
Falk  D;  Wang  XQ;  Liu  L;  Fertig  J;  Mattson  M;  Ryan  M;  Johnson  B;  Stout  R;  Litten  RZ:  Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials.  Alcohol Clin Exp Res 2010; 34:2022–2034
[CrossRef] | [PubMed]
 
Gratacòs  M;  González  JR;  Mercader  JM;  de Cid  R;  Urretavizcaya  M;  Estivill  X:  Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia.  Biol Psychiatry 2007; 61:911–922
[CrossRef] | [PubMed]
 
Pooley  EC;  Fairburn  CG;  Cooper  Z;  Sodhi  MS;  Cowen  PJ;  Harrison  PJ:  A 5-HT2C receptor promoter polymorphism (HTR2C-759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes.  Am J Med Genet B Neuropsychiatr Genet 2004; 126B:124–127
[CrossRef] | [PubMed]
 
Lee  HS;  Kim  SH;  Lee  HJ;  Kim  L;  Lee  SK;  Jang  DW;  Lee  MS;  Son  BG;  Suh  KY;  Kim  S:  Gender-specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia.  Am J Med Genet 2002; 114:593–597
[CrossRef] | [PubMed]
 
Retz  W;  Rösler  M;  Supprian  T;  Retz-Junginger  P;  Thome  J:  Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology.  J Neural Transm 2003; 110:561–572
[CrossRef] | [PubMed]
 
Gosso  MF;  de Geus  EJ;  Polderman  TJ;  Boomsma  DI;  Heutink  P;  Posthuma  D:  Catechol O-methyl transferase and dopamine D2 receptor gene polymorphisms: evidence of positive heterosis and gene-gene interaction on working memory functioning.  Eur J Hum Genet 2008; 16:1075–1082
[CrossRef] | [PubMed]
 
Szabo  G;  Mandrekar  P:  Ethanol-mediated regulation of transcription factors in immunocompetent cells.  Front Biosci 2002; 7:a80–a89
[CrossRef] | [PubMed]
 
Wang  H;  Zhou  H;  Chervenak  R;  Moscatello  KM;  Brunson  LE;  Chervenak  DC;  Wolcott  RM:  Ethanol exhibits specificity in its effects on differentiation of hematopoietic progenitors.  Cell Immunol 2009; 255:1–7
[CrossRef] | [PubMed]
 
Windemuth  A;  Calhoun  VD;  Pearlson  GD;  Kocherla  M;  Jagannathan  K;  Ruaño  G:  Physiogenomic analysis of localized fMRI brain activity in schizophrenia.  Ann Biomed Eng 2008; 36:877–888
[CrossRef] | [PubMed]
 
Souza  RP;  de Luca  V;  Meltzer  HY;  Lieberman  JA;  Kennedy  JL:  Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia.  Pharmacogenet Genomics 2010; 20:274–276
[PubMed]
 
Brüss  M;  Eucker  T;  Göthert  M;  Bönisch  H:  Exon-intron organization of the human 5-HT3A receptor gene.  Neuropharmacology 2000; 39:308–315
[CrossRef] | [PubMed]
 
Seneviratne  C;  Franklin  J;  Beckett  K;  Ma  JZ;  Ait-Daoud  N;  Payne  TJ;  Johnson  BA;  Li  MD:  Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence.  Hum Genet  (in press)
 
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