Significant association of DRD2 and ANKK1 genes with rural heroin dependence and relapse in men
More details
Hide details
Department of Physical Education and Social Science, University of Physical Education and Sport, Gdańsk, Poland
Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, Poland
Independent Laboratory of Health Promotion of the Pomeranian Medical University, Szczecin, Poland
Neurophysiological Independent Unit, Department of Psychiatry, Medical University, Lublin, Poland
Department of Humanities in Medicine, Pomeranian Medical University, Szczecin, Poland
Independent Laboratory of Family Physician Education, Pomeranian Medical University, Szczecin, Poland
Pomeranian Medical University, Szczecin, Poland
Anna Grzywacz   

Independent Laboratory of Health Promotion of the Pomeranian Medical University in Szczecin, Chłapowskiego 11, 70-103, Szczecin, Poland
Substance abuse significantly influences human health and may induce problems with social functioning worldwide. Numerous genetic and environmental risk factors, as well as their interactions, accelerate the development of drug addiction. Etiologically, the dopaminergic mesocorticolimbic reward pathways are related to psychoactive substance addiction, and the reward properties of heroin are connected with changes in the mesolimbic dopaminergic system.

The aim of this study is a haplotypic analysis of subjects addicted to polysubstance. However, with the knowledge that this is not a homogenous subgroup, it was decided to separate and analyze homogenous subgroups of subjects in order to find specific haplotypic variants among them. The subjects in the subgroups were addicted to heroin, and subjects with more than two relapses in the past two years.

Material and methods:
The study group comprised of 301 polysubstance addicted rural male subjects. From this group, 2 homogenous subgroups of subjects were isolated and additionally analyzed: (1) a group of heroin addicted subjects (n=61), and (2) a group of heroin-addicted subjects with at least two relapses in the last two years (n=21). The group consisting of all polysubstance addicted rural subjects and both homogenous subgroups were analyzed against a control group of non-addicted subjects (n=300), matching gender and age. Five polymorphisms in the DRD2/ANKK1 region were analyzed: rs1076560, rs1800498, rs1079597, rs6276 in the DRD2 gene, and rs1800497 in the ANKK1 gene.

A statistically significant haplotype association was found in analysis of the heroin addicted subjects, compared to controls, and two possible trends – when comparing the whole group of addicted subjects to controls, and in relapse subgroups, compared to the controls.

The results obtained showed that haplotypes indicate a part of the biological component of addiction.

This research was funded by National Science Centre, Poland, grant number UMO-2015/19/B/NZ7/03691.
Vereczkey A, Demetrovics Z, Szekely A, Sarkozy P, Antal P Szilagyi A, et al. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence. PLoS One. 2013; 8e66592.
Levran O, Randesi M, da Rosa JC, Ott J, Rotrosen J, Adelson M, et al. Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans. Ann Hum Genet. 2015; 79: 188–98.
Burns JA, Kroll DS, Feldman DE, Kure Liu C, Manza P, Wiers CE, et al. Molecular Imaging of Opioid and Dopamine Systems: Insights into the Pharmacogenetics of Opioid Use Disorders. Front Psychiatry. 2019; 10: 626.
Zhou Y, Leri F, Cummins E, Kreek MJ. Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin-seeking in rats. Physiol Behav. 2015; 139: 127–135.
Solinas M, Belujon P, Fernagut PO, Jaber M, Thiriet N. Dopamine and addiction: what have we learned from 40 years of research. J Neural Transm (Vienna). 2019; 126: 481–516.
Keramati M, Gutkin B. Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit. PLoS One. 2013; 8: e61489.
Ikemoto S, Bonci A. Neurocircuitry of drug reward. Neuropharmacology. 2014; 76 Pt B: 329–41.
Girault JA. Signaling in striatal neurons: the phosphoproteins of reward, addiction, and dyskinesia. Prog Mol Biol Transl Sci. 2012; 106: 33–62.
Chen YH, Lin BJ, Hsieh TH, Kuo TT, Miller J, Chou YC, et al. Differences in Nicotine Encoding Dopamine Release between the Striatum andShell Portion of the Nucleus Accumbens. Cell Transplant. 2019; 28: 248–261.
Patriquin MA, Bauer IE, Soares JC, Graham DP, Nielsen DA. Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system. Psychiatr Genet. 2015; 25: 181–93.
Linden J, James AS, McDaniel C, Jentsch JD. Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice. eNeuro. 2018; 5: pii: ENEURO.0229-17.2018.
Sznabowicz M, Jasiewicz A, Iskra-Trifunović J, Małecka I, Karakiewicz B, Kotwas A, et al. Case-control study analysis of DRD2 gene polymorphisms in drug addicted patients. Psychiatr Pol. 2018; 52: 1013–1022.
Mota NR, Araujo-Jnr EV, Paixao-Cortes VR, Bortolini MC, Bau CH. Linking dopamine neurotransmission and neurogenesis: The evolutionary history of the NTAD (NCAM1-TTC12-ANKK1-DRD2) gene cluster. Genet Mol Biol. 2012; 35: 912–8.
Grandy DK, Litt M, Allen L, Bunzow JR, Marchionni M, Makam H, et al. The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. Am J Hum Genet, 1989; 45: 778–785.
Wagner AK, Scanlon JM, Becker CR, Ritter AC, Niyonkuru C, Dixon CE, et al. The influence of genetic variants on striatal dopamine transporter and D2 receptor binding after TBI. J Cereb Blood Flow Metab. 2014; 34: 1328–39.
Grzywacz A, Chmielowiec J, Chmielowiec K, Mroczek B, Masiak J, Suchanecka A, et al. The Ankyrin Repeat and Kinase Domain Containing 1 Gene Polymorphism (ANKK1 Taq1A) and Personality Traits in Addicted Subjects. Int J Environ Res Public Health. 2019; 16: pii: E2687.
Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: Glia, the unacknowledged partner. Trends Neurosc. 1999; 22: 208–215.
Meylan E, Tschopp J. The RIP kinases: Crucial integrators of cellular stress. Trends Biochem Sc 2005; 30: 151–159.
Huang W, Payne TJ, Ma JZ, Beuten J, Dupont RT, Inohara N, Li MD. Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African American Sample. Neuropsychopharmacology. 2009; 34: 319–330.
Jasiewicz A, Samochowiec A, Samochowiec J, Małecka I, Suchanecka A, Grzywacz A. Suicidal behavior and haplotypes of the dopamine receptor gene (DRD2) and ANKK1 gene polymorphisms in patients with alcohol dependence--preliminary report. PLoS One. 2014; 9: e111798.
Huang SY, Lin WW, Ko HC, Lee JF, Wang TJ, Chou YH, et al. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcohol Clin Exp Res. 2004; 28: 374–384.
Arinami T, Gao M, Hamaguchi H, Toru M. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet. 1997; 6: 577–582.
Ma Y, Yuan W, Jiang X, Cui WY, Li MD. Updated findings of the association and functional studies of DRD2/ANKK1 variants with addictions. Mol Neurobiol. 2015; 51: 281–99.
Tsou CC, Chou HW, Ho PS, Kuo SC, Chen CY, Huang CC, et al. DRD2 and ANKK1 genes associate with late-onset heroin dependence in men. World J Biol Psychiatry. 2019; 20: 605–615.
Spellicy CJ, Harding MJ, Hamon SC, Mahoney JJ 3rd, Reyes JA, Kosten TR, et al. A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study. Genes Brain Behav. 2014; 13: 559–64.
Mignini F, Napolioni V, Codazzo C, Carpi FM, Vitali M, Romeo M, et al. DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: association and gene-gene interaction study in a population of Central Italy. Neurosci Lett. 2012; 522: 103–107.
Voisey J, Swagell CD, Hughes IP, van Daal A, Noble EP, Lawford BR, et al. A DRD2 and ANKK1 haplotype is associated with nicotine dependence. Psychiatry Res. 2012; 196: 285–9.
Xu K, Lichtermann D, Lipsky RH, Franke P, Liu X, Hu Y, et al. Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry. 2004; 61: 597–606.
Blum K, Noble EP, Sheridan PJ, Montgomery A, Ritchie T, Ozkaragoz T, et al. Genetic predisposition in alcoholism: association of the D2 dopamine receptor TaqI B1 RFLP with severe alcoholics. Alcohol. 1993; 10: 59–67.
Smith SS, O’Hara BF, Persico AM, Gorelick DA, Newlin DB, Vlahov D, et al. Genetic vulnerability to drug abuse. The D2 dopamine receptor Taq I B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers. Arch Gen Psychiatry. 1992; 49: 723–727.
Ponce G, Quiñones-Lombraña A, Martín-Palanco NG, Rubio-Solsona E, Jiménez-Arriero MA, Palomo T, et al. The Addiction-Related Gene Ankk1 is Oppositely Regulated by D1R- and D2R-Like Dopamine Receptors. Neurotox Res. 2016; 29: 345–50.
Al-Eitan LN, Jaradat SA, Hulse GK, Tay G. Custom genotyping for substance addiction susceptibility genes in Jordanians of Arab descent. BMC Res Notes. 2012; 5: 497.
Clarke TK, Weiss AR, Ferarro TN, Kampman KM, Dackis CA, Pettinati HM, et al. The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction. Ann Hum Genet. 2014; 78: 33–39.
Jacobs MM, Murray J, Byrd DA, Hurd YL, Morgello S. HIV-related cognitive impairment shows bi-directional association with dopamine receptor DRD1 and DRD2 polymorphisms in substance-dependent and substance-independent populations. J Neurovirol. 2013; 19: 495–504.
Zhang J, Yan P, Li Y, Cai X, Yang Z, Miao X, et al. A 35.8 kilobases haplotype spanning ANKK1 and DRD2 is associated with heroin dependence in Han Chinese males. Brain Res. 2018; 1688: 54–64.
Jabeen S, Pinsonneault JK, Sadee W, Lee SH, Zafar MM, Raja MS, et al. Significant association of DRD2 enhancer variant rs12364283 with heroin addiction in a Pakistani population. Ann Hum Genet. 2019; 83: 367–372.
Nelson EC, Lynskey MT, Heath AC, Wray N, Agrawal A, Shand FL, et al. ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure. JAMA Psychiatry. 2013; 70: 325–333.
Stolf AR, Cupertino RB, Müller D, Sanvicente-Vieira B, Roman T, et al. Effects of DRD2 splicing-regulatory polymorphism and DRD4 48 bp VNTR on crack cocaine addiction. J Neural Transm (Vienna). 2019; 126: 193–199.
Sullivan D, Pinsonneault JK, Papp AC, Zhu H, Lemeshow S, et al. Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction. Transl Psychiatry. 2013; 3: e222.
Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsycho-pharmacology. 2010; 35: 217–238.
Noble EP. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. Eur J Psychiatr. 2000; 15: 79–89.
Radwan GN, El-Setouhy M, Mohamed MK, Hamid MA, Azem SA, Kamel O, et al. DRD2/ANKK1 TaqI polymorphism and smoking behavior of Egyptian male cigarette smokers. Nicotine Tobacco Res. 2007; 9: 1325–1329.
Gelernter J, Yu Y, Weiss R, Brady K, Panhuysen C, Yang BZ, 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.
Yang BZ, Kranzler HR, Zhao H, Gruen JR, Luo X, Gelernter J, et al. Haplotypic variants in DRD2, ANKK1, TTC12, and NCAM1 are associated with comorbid alcohol and drug dependence. Alcohol Clin Exp Res. 2008; 32; 2117–2127.
Gluskin BS, Mickey BJ. Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies. Transl Psychiatry. 2016; 6: e747.
Jönsson EG, Nöthen MM, Grünhage F, Farde L, Abumrad NN, Hitzemann RJ, 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.
Wang GJ, Volkow ND, Fowler JS, Logan J, Abumard NN, Hitzemann RJ, et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsycho -pharmacology. 1997; 16: 174–182.
Kukreti R, Tripathi S, Bhatnagar P, Gupta S, Chauhan C, Kubendran S, et al. Association of DRD2 gene variant with schizophrenia. Neurosci Lett. 2006; 392: 68–71.
Doehring A, Hentig NV, Graff J, Salamat S, Schmidt M, Geisslinger G, et al. Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution. Pharmacogenet Genomics. 2009; 19: 407–414.
Iida K, Akashi H. A test of translational selection at ‘silent’ sites in the human genome: base composition comparisons in alternatively spliced genes. Gene. 2000; 261: 93–105.
Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, 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.