Distinct Haplogenotypes of the Dopamine D2 Receptor Gene are Associated with Non-smoking Behaviour and Daily Cigarette Consumption

 

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Abstract

Introduction: Dopamine systems in the CNS are decisively implicated in the motivational and rewarding properties of nicotine. The dopamine D2 receptor (DRD2) plays a pivotal role by promoting these properties, making this gene a good candidate for association studies. Several single nucleotide polymorphisms (SNPs) have been described to influence the expression of DRD2. The amount of expressed DRD2 will finally be the result of the sum and/or interaction of several functional polymorphisms located at the respective DNA strand forming a distinct haplotype. Thus, the knowledge about the distribution of the haplotypes in groups of subjects, differing by their smoking behaviour, would result in a better understanding of the putative associations compared to single SNP investigations.

Methods: 218 healthy subjects grouped for being never smokers, former smokers, and current smokers, were genotyped for the following polymorphisms: −141 ins(I)/del(D), STRPi2 (intron 2), C957T (exon 7), A1385G (exon 8), and TaqIA. Regular immoderate alcohol consumption was an exclusion criterion.

Results: In the total study group four haplotypes represented 90% of the haplotypes, with I-T-A-A2, I-C-G-A2, I-C-A-A1, and D-C-G-A2 accounting for around 50%, 20%, 10%, and 10%, respectively. I-C-G-A2 homozygosity was significantly higher in never smokers compared to ever smokers (current+former smokers) (χ²=36.585, df=1, p<0.001). There was a significant difference in the daily cigarette consumption of current smokers with respect to the haplogenotype (χ²=3211.9, df=18, p=0.003). Current smokers with a haplogenotype containing at least one I-T-A-A2 allele showed a significant smaller daily cigarette consumption (15.1±7.93) compared to subjects with a genotype not bearing this allele (20.1±6.79; T=−2.06, df=61, p=0.044).

Conclusion: We have demonstrated an association of the distinct haplogenotype I/I-C/C-G/G-A2/A2 of the DRD2 gene with a reduced risk to become a smoker in Caucasians of German origin. This protection may result from an association of this haplotype with a reduced activation of the dopaminergic neurotransmission by nicotine. Moreover, in current smokers, higher daily cigarette consumption is associated with those haplogenotypes that do not contain the I-T-A-A2 haplotype.

References

• 1 Albert PR. Heterologous expression of G protein-linked receptors in pituitary and fibroblast cell lines.  Vitam Horm. 1994;  48 59-109 , [Review]
  PubMedGoogle Scholar
• 2 American Cancer Society .Cancer facts and figures Atlanta. GA: American Cancer Society 2004
• 3 Arinami T, Gao M, Hamaguchi H. et al . A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia.  Hum Mol Genet. 1997;  6 577-582
  CrossrefPubMedGoogle Scholar
• 4 Bardel C, Danjean V, Génin E. ALTree: association detection and localization of susceptibility sites using haplotype phylogenetic trees.  Bioinformatics applications note. 2006;  22 1402-1403
  PubMedGoogle Scholar
• 5 Barrett JC, Try B, Maller J. et al . Haploview: analysis and visualization of LD and haplotype maps.  Bioinformatics. 2005;  21 263-265
  CrossrefPubMedGoogle Scholar
• 6 Brody AL, Olmstead RE, London ED. et al . Smoking-induced ventral striatum dopamine release.  Am J Psychiatry. 2004;  161 1211-1218
  CrossrefPubMedGoogle Scholar
• 7 Carmelli D, Swan GE, Robinette D. et al . Genetic influence on smoking – a study of male twins.  N Engl J Med. 1992;  327 829-833
  PubMedGoogle Scholar
• 8 Center for Disease Control and Prevention . Annual smoking-attributable mortality, years of potentional life cost, and economic costs – United States, 1995–1999.  Morbidity and Mortality Weekly Report. 2002;  51 300-303
  PubMedGoogle Scholar
• 9 Civelli O, Bunzow JR, Grandy DK. Molecular diversity of the dopamine receptors.  Annu Rev Pharmacol Toxicol. 1993;  33 281-307 , [Review]
  CrossrefPubMedGoogle Scholar
• 10 Corrigall WA, Coen KM, Adamson KL. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area.  Brain Res. 1994;  653 278-284
  CrossrefPubMedGoogle Scholar
• 11 Chiara G Di. Role of dopamine in the behavioural actions of nicotine related to addiction.  Eur J Pharmacol. 2000;  393 295-314 , [Review]
  CrossrefPubMedGoogle Scholar
• 12 Duan J, Wainwright MS, Comeron JM. et al . Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor.  Hum Mol Genet. 2003;  12 205-216
  CrossrefPubMedGoogle Scholar
• 13 Durstewitz D. A few important points about dopamine's role in neural network dynamics.  Pharmacopsychiatry. 2006;  39 ((Suppl 1)) S72-S75
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Finckh U, Rommelspacher H, Kuhn S. et al . Influence of the dopamine D2 receptor (DRD2) genotype on neuroadaptive effects of alcohol and the clinical outcome of alcoholism.  Pharmacogenetics. 1997;  7 271-281
  CrossrefPubMedGoogle Scholar
• 15 Gallinat J, Mulert C, Bajbouj M. et al . Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia.  Neuroimage. 2002;  17 110-127
  CrossrefPubMedGoogle Scholar
• 16 Gallinat J, Meisenzahl E, Jacobsen LK. et al . Smoking and structural brain deficits: a volumetric MR investigation.  Eur J Neurosci. 2006;  24 1744-1750
  CrossrefPubMedGoogle Scholar
• 17 Gallinat J, Lang UE, Jacobsen LK. et al . Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3T.  J Clin Psychopharmacol. 2007;  27 80-84
  CrossrefPubMedGoogle Scholar
• 18 Gallinat J, Schubert F. Regional cerebral glutamate concentrations and chronic tobacco consumption.  Pharmacopsychiatry. 2007;  40 64-67
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Gardner EL. Brain reward mechanisms. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds. Substance abuse: A Comprehensive Textbook, 4th Ed. Philadelphia: Lippincott Williams and Wilkins 2005: 48-97
  Google Scholar
• 20 Gelernter J, Yu Y, Weiss R. et al . Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations.  Hum Mol Genet. 2006;  15 3498-3507
  CrossrefPubMedGoogle Scholar
• 21 Gingrich JA, Caron MG. Recent advances in the molecular biology of dopamine receptors.  Annu Rev Neurosci. 1993;  16 299-321 , [Review]
  PubMedGoogle Scholar
• 22 Heath AC, Martin NG. Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence.  Addict Behav. 1993;  18 19-34 , [Review]
  CrossrefPubMedGoogle Scholar
• 23 Heatherton TF, Kozlowski LT, Frecker RC. et al . The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire.  Br J Addict. 1991;  86 1119-1127
  CrossrefPubMedGoogle Scholar
• 24 Hirvonen M, Laakso A, Någren K. et al . C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo.  Mol Psychiatry. 2004;  9 1060-1051 , Erratum in: Mol Psychiatry 2005;10: 889
  CrossrefPubMedGoogle Scholar
• 25 Hwang R, Shinkai T, Luca V De. et al . Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations.  Psychopharmacology (Berl). 2005;  181 179-187
  CrossrefPubMedGoogle Scholar
• 26 Ikemoto S, Glazier BS, Murphy JM. et al . Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward.  J Neurosci. 1997;  17 8580-8587
  PubMedGoogle Scholar
• 27 Imperato A, Mulas A, Chiara G Di. Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats.  Eur J Pharmacol. 1986;  132 337-338
  CrossrefPubMedGoogle Scholar
• 28 Jacobsen LK, Pugh KR, Mencl WE. et al . C957T polymorphism of the dopamine D2 receptor gene modulates the effect of nicotine on working memory performance and cortical processing efficiency.  Psychopharmacology (Berl). 2006;  188 530-540
  CrossrefPubMedGoogle Scholar
• 29 Jönsson EG, Nöthen MM, Grünhage F. et al . Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.  Mol Psychiatry. 1999;  4 290-296
  CrossrefPubMedGoogle Scholar
• 30 Kendler KS, Neale MC, MacLean CJ. et al . Smoking and major depression. A causal analysis.  Arch Gen Psychiatry. 1993;  50 36-43
  CrossrefPubMedGoogle Scholar
• 31 Khan ZU, Mrzljak l, Gutierrez A. et al . Prominence of the dopamine D2 short isoform in dopaminergic pathways.  Proc Natl Acad Sci USA. 1998;  95 7731-7736
  CrossrefPubMedGoogle Scholar
• 32 Kidd KK, Morar B, Castiglione CM. et al . A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus.  Hum Genet. 1998;  103 211-227
  PubMedGoogle Scholar
• 33 Kirsch P, Reuter M, Mier D. et al . Imaging gene-substance interactions: the effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward.  Neurosci Lett. 2006;  25; 405 196-201
  PubMedGoogle Scholar
• 34 Laakso A, Pohjalainen T, Bergman J. et al . The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects.  Pharmacogenet Genomics. 2005;  15 387-391
  CrossrefPubMedGoogle Scholar
• 35 Lang UE, Hellweg R, Gallinat J. Association of BDNF serum concentrations with central serotonergic activity: evidence from auditory signal processing.  Neuropsychopharmacology. 2005;  30 1148-1153
  CrossrefPubMedGoogle Scholar
• 36 Lang UE, Sander T, Lohoff FW. et al . Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking.  Psychopharmacology (Berl). 2007;  190 433-439
  CrossrefPubMedGoogle Scholar
• 37 Lerman C, Jepson C, Wileyto EP. et al . Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials.  Neuropsychopharmacology. 2006;  31 231-242
  PubMedGoogle Scholar
• 38 Leuner K, Müller WE. The complexity of the dopaminergic synapses and their modulation by antipsychotics.  Pharmacopsychiatry. 2006;  39 ((Suppl 1)) S15-S20
  Article in Thieme ConnectPubMedGoogle Scholar
• 39 Li MD, Cheng R, Ma JZ. et al . A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins.  Addiction. 2003;  98 23-31 , [Review]
  CrossrefPubMedGoogle Scholar
• 40 Li MD, Ma JZ, Beuten J. Progress in searching for susceptibility loci and genes for smoking-related behaviour.  Clin Genet. 2004;  66 382-392 , [Review]
  CrossrefPubMedGoogle Scholar
• 41 Lucht MJ, Kuehn KU, Schroeder W. et al . Influence of the dopamine D2 receptor (DRD2) exon 8 genotype on efficacy of tiapride and clinical outcome of alcohol withdrawal.  Pharmacogenetics. 2001;  11 647-653
  CrossrefPubMedGoogle Scholar
• 42 Luo HR, Hou ZF, Wu J. et al . Evolution of the DRD2 gene haplotype and its association with alcoholism in Mexican Americans.  Alcohol. 2005;  36 117-125
  CrossrefPubMedGoogle Scholar
• 43 Mercuri NB, Saiardi A, Bonci A. et al . Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice.  Neuroscience. 1997;  79 323-327
  CrossrefPubMedGoogle Scholar
• 44 Miller SA, Dykes S, Plesky HF. A simple salting out procedure for extracting DNA from human nucleated cells.  Nucleic Acids Res. 1988;  16 1215
  CrossrefPubMedGoogle Scholar
• 45 Montmayeur JP, Guiramand J, Borelli E. Preferential coupling between dopamine D2 receptors and G-proteins.  Mol Endo. 1993;  163 161-170
  PubMedGoogle Scholar
• 46 Morton LM, Wang SS, Bergen AW. et al . DRD2 genetic variation in relation to smoking and obesity in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.  Pharmacogenet Genomics. 2006;  16 901-910
  CrossrefPubMedGoogle Scholar
• 47 Nakajima S, Liu X, Lau CL. Synergistic interaction of D1 and D2 dopamine receptors in the modulation of the reinforcing effect of brain stimulation.  Behav Neurosci. 1993;  107 161-165
  CrossrefPubMedGoogle Scholar
• 48 Neuhaus A, Bajbouj M, Kienast T. et al . Persistent dysfunctional frontal lobe activation in former smokers.  Psychopharmacology (Berl). 2006;  186 191-200
  CrossrefPubMedGoogle Scholar
• 49 Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1.  Hum Mutat. 2004;  23 540-545
  CrossrefPubMedGoogle Scholar
• 50 Noble EP, Blum K, Ritchie T. et al . Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism.  Arch Gen Psychiatry. 1991;  48 648-654
  PubMedGoogle Scholar
• 51 Noble EP, Gottschalk LA, Fallon JH. et al . D2 dopamine receptor polymorphism and brain regional glucose metabolism.  Am J Med Genet. 1997;  74 162-166
  CrossrefPubMedGoogle Scholar
• 52 Noble EP. The DRD2 gene in psychiatric and neurological disorders and its phenotypes.  Pharmacogenomics. 2000;  1 309-333 , [Review]
  CrossrefPubMedGoogle Scholar
• 53 Pohjalainen T, Rinne JO, Någren K. et al . The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers.  Mol Psychiatry. 1998;  3 256-260
  CrossrefPubMedGoogle Scholar
• 54 Pontieri FE, Tanda G, Orzi F. et al . Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs.  Nature. 1996;  382 255-257
  CrossrefPubMedGoogle Scholar
• 55 Rein M. Funktionelle Analyse der 3′ untranslatierten Region des Dopamin D2 Rezeptor Gens. Dissertationsschrift. Institut für Humangenetik, Universitätsklinikum Hamburg Eppendorf 2008
• 56 Rohde K, Fürst R. Haplotyping and estimation of haplotype frequencies for closely linked biallelic multilocus genetic phenotypes including nuclear family information.  Hum Mutat. 2001;  17 289-295
  CrossrefPubMedGoogle Scholar
• 57 Thompson J, Thomas N, Singleton A. et al . D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele.  Pharmacogenetics. 1997;  7 479-484
  CrossrefPubMedGoogle Scholar
• 58 Usiello A, Baik JH, Rouge-Pont F. et al . Distinct functions of the two isoforms of dopamine D2 receptors.  Nature. 2000;  408 199-203
  CrossrefPubMedGoogle Scholar
• 59 Wise RA, Gardner EL. Functional anatomy of substance-related disorders. In: D’haenen H, den Boer JA, Willner P, eds. Biological Psychiatry. Wiley, New York 2002: 509-522
  Google Scholar
• 60 Zhang Y, Bertolino A, Fazio L. et al . Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.  Proc Natl Acad Sci USA. 2007;  104 20552-20557
  CrossrefPubMedGoogle Scholar

Correspondence

Dr. rer. nat. C. Wernicke

Charité – Universitätsmedizin Berlin

Campus Benjamin Franklin

Klinik für Psychiatrie und Psychotherapie

Bereich Klinische Neurobiologie

Eschenallee 3

14050 Berlin

Germany

Phone: +49/30/8445 82 57

Fax: +49/30/8445 82 44

Email: catrin.wernicke@charite.de