Review

Genetic variation in alcoholism and opioid addiction susceptibility and treatment: a pharmacogenomic approach

  • Received: 12 July 2021 Accepted: 29 September 2021 Published: 09 October 2021
  • Alcohol and opioid abuse have pervasive and detrimental consequences from the individual to societal level. The extent of genetic contribution to alcoholism has been studied for decades, yielding speculative and often inconsistent results since the previous discovery of two pharmacokinetic variants strongly protective against alcoholism. The neurobiology of addiction involves innumerate genes with combinatorial and epistatic interactions, creating a difficult landscape for concrete conclusions. In contrast, pharmacogenomic variation in the treatment of alcoholism yields more immediate clinical utility, while also emphasizing pathways crucial to the progression of addiction. An improved understanding of genetic predisposition to alcohol abuse has inherent significance for opioid addiction and treatment, as the two drugs induce the same reward pathway. This review outlines current knowledge, treatments, and research regarding genetic predisposition to alcoholism, focusing on pharmacodynamic variation within the dopaminergic system and shared implications for opioid abuse. Multifaceted and highly polygenic, the phenotype of addiction seems to grow more complex as new research extends the scope of its impact on the brain, body, and progeny.

    Citation: Catherine Demery-Poulos, Joseph M. Chambers. Genetic variation in alcoholism and opioid addiction susceptibility and treatment: a pharmacogenomic approach[J]. AIMS Molecular Science, 2021, 8(4): 202-222. doi: 10.3934/molsci.2021016

    Related Papers:

  • Alcohol and opioid abuse have pervasive and detrimental consequences from the individual to societal level. The extent of genetic contribution to alcoholism has been studied for decades, yielding speculative and often inconsistent results since the previous discovery of two pharmacokinetic variants strongly protective against alcoholism. The neurobiology of addiction involves innumerate genes with combinatorial and epistatic interactions, creating a difficult landscape for concrete conclusions. In contrast, pharmacogenomic variation in the treatment of alcoholism yields more immediate clinical utility, while also emphasizing pathways crucial to the progression of addiction. An improved understanding of genetic predisposition to alcohol abuse has inherent significance for opioid addiction and treatment, as the two drugs induce the same reward pathway. This review outlines current knowledge, treatments, and research regarding genetic predisposition to alcoholism, focusing on pharmacodynamic variation within the dopaminergic system and shared implications for opioid abuse. Multifaceted and highly polygenic, the phenotype of addiction seems to grow more complex as new research extends the scope of its impact on the brain, body, and progeny.


    Abbreviations

    ADH1B

    alcohol dehydrogenase 1B

    ADH1C

    alcohol dehydrogenase 1C

    ALDH2

    aldehyde dehydrogenase 2

    AUD

    alcohol use disorder

    AUDIT-C

    Alcohol Use Disorder Identification Test – Consumption

    Ca-AOTA

    calcium-bis (N-acetylhomotaurinate)

    CYP2E1

    cytochrome P450 family 2, subfamily e, polypeptide 1

    DMC

    differentially-methylated cytosine

    DRD2

    dopamine receptor D2

    FAM107B

    family with sequence similarity 107 member B

    FICD

    FIC domain protein adenylyltransferase

    FTO

    fat, mass, and obesity-associated gene

    FUT2

    fucosyltransferase 2

    GABA

    gamma aminobutyric acid

    GCKR

    glucokinase receptor

    GPCR

    G-protein coupled receptor

    GWAS

    genome-wide association study

    KCa

    calcium-activated potassium channel

    KCNB1 (KV2.1)

    potassium voltage-gated channel subfamily B member 1

    KCNMA1 (KCa1.1)

    potassium calcium-activated channel subfamily M alpha 1

    KCNQ5 (KV7.5)

    potassium voltage-gated channel subfamily Q member 5

    KIR

    inwardly-rectifying potassium channel

    KIF2

    kinesin family member 2A

    KLB

    klotho beta

    KOR

    kappa opioid receptor

    KV

    voltage-dependent potassium channel

    LOC257642

    rRNA promoter binding protein

    MAD2L2

    mitotic arrest deficient 2 like 2

    NAc

    nucleus accumbens

    NDMA

    N-methyl-D-aspartate

    OPRM1

    µ opioid receptor 1

    ORC4

    origin recognition complex subunit 4

    PDE4B

    cAMP-specific 3′,5′-cyclic phosphodiesterase 4B

    PFC

    prefrontal cortex

    PPAP2B

    phosphatidate phosphohydrolase type 2b

    PTPRM

    protein tyrosine phosphatase receptor type M

    RDS

    Reward Deficiency Syndrome

    RNF165

    ring finger protein 165

    SIX3

    SIX homeobox 3

    SLC39A8

    solute carrier family 39 member 8

    SLC39A13

    solute carrier family 39 member 13

    VTA

    ventral tegmental area

    WBSCR17

    polypeptide N-acetylgalactosaminyltransferase 17

    加载中


    Conflict of interest



    The authors declare no conflict of interest in this paper.

    [1] Addiction Merriam-Webster Available from: https://www.merriam-webster.com/dictionary/addiction.
    [2]  Deaths from Excessive Alcohol Use in the U.S. Centers for Disease Control and Prevention, 2020 Available from: https://www.cdc.gov/alcohol/features/excessive-alcohol-deaths.html.
    [3] Overdose Death Rates National Institute on Drug Abuse, 2020 Available from: https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates.
    [4] Costs of Substance Abuse National Institute on Drug Abuse, 2020 Available from: https://archives.drugabuse.gov/trends-statistics/costs-substance-abuse.
    [5] Bettinardi-Angres K, Angres D (2010) Understanding the Disease of Addiction. J Nurs Regul 1: 31-37. doi: 10.1016/S2155-8256(15)30348-3
    [6] Alcohol Addiction National Institute on Drug Abuse, 2020 Available from: https://www.drugabuse.gov/drug-topics/alcohol.
    [7] Bilbao A, Robinson JE, Heilig M, et al. (2015) A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. Biol Psychiatry 77: 850-858. doi: 10.1016/j.biopsych.2014.08.021
    [8] Matsumura Y, Stiles KM, Reid J, et al. (2019) Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency. Mol Ther Methods Clin Dev 15: 72-82. doi: 10.1016/j.omtm.2019.08.004
    [9] Kisor DF, Bright DR, Smith TR, et al. Pharmacogenomics Foundations, Competencies, and the Pharmacists' Patient Care Process: APhA (2020) . doi: 10.21019/9781582123127
    [10] Ducci F, Goldman D (2012) The genetic basis of addictive disorders. Psychiatr Clin North Am 35: 495-519. doi: 10.1016/j.psc.2012.03.010
    [11] Maldonado R, Calvé P, García-Blanco A, et al. (2021) Genomics and epigenomics of addiction. Am J Med Genet, Part B 186: 128-139. doi: 10.1002/ajmg.b.32843
    [12] Kranzler HR, Zhou H, Kember RL, et al. (2019) Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations. Nat Commun 10: 1499. doi: 10.1038/s41467-019-09480-8
    [13] Hancock DB, Levy JL, Gaddis NC, et al. (2015) Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1. Biol Psychiatry 78: 474-484. doi: 10.1016/j.biopsych.2015.01.003
    [14] Hill SY, Tessner KD, McDermott MD (2011) Psychopathology in offspring from families of alcohol dependent female probands: a prospective study. J Psychiatr Res 45: 285-294. doi: 10.1016/j.jpsychires.2010.08.005
    [15] Asimes A, Torcaso A, Pinceti E, et al. (2017) Adolescent binge-pattern alcohol exposure alters genome-wide DNA methylation patterns in the hypothalamus of alcohol-naïve male offspring. Alcohol 60: 179-189. doi: 10.1016/j.alcohol.2016.10.010
    [16] Froehlich JC (1997) Opioid peptides. Alcohol Health Res World 21: 132-136.
    [17] Patriquin MA, Bauer IE, Soares JC, et al. (2015) Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system. Psychiatr Genet 25: 181-193. doi: 10.1097/YPG.0000000000000095
    [18] Nutt D (2016) Mechanisms of Addiction. London Centre for Neuropsychopharmacology: Tocris Bioscience .
    [19] Anderson RI, Becker HC (2017) Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol. Alcohol: Clin Exp Res 41: 1402-1418. doi: 10.1111/acer.13406
    [20] Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology 86: 274-280. doi: 10.1007/BF00432213
    [21] Nylander I, Hyytiä P, Forsander O, et al. (1994) Differences between alcohol-preferring (AA) and alcohol-avoiding (ANA) rats in the prodynorphin and proenkephalin systems. Alcohol: Clin Exp Res 18: 1272-1279. doi: 10.1111/j.1530-0277.1994.tb00118.x
    [22] LeDoux JE (1993) Emotional memory systems in the brain. Behav Brain Res 58: 69-79. doi: 10.1016/0166-4328(93)90091-4
    [23] Alasmari F, Goodwani S, McCullumsmith RE, et al. (2018) Role of glutamatergic system and mesocorticolimbic circuits in alcohol dependence. Prog Neurobiol 171: 32-49. doi: 10.1016/j.pneurobio.2018.10.001
    [24] Trantham-Davidson H, Neely LC, Lavin A, et al. (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24: 10652-10659. doi: 10.1523/JNEUROSCI.3179-04.2004
    [25] Perry JL, Joseph JE, Jiang Y, et al. (2011) Prefrontal cortex and drug abuse vulnerability: translation to prevention and treatment interventions. Brain Res Rev 65: 124-149. doi: 10.1016/j.brainresrev.2010.09.001
    [26] Clapp P, Bhave SV, Hoffman PL (2008) How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health 31: 310-339.
    [27] Leyton M, Vezina P (2014) Dopamine ups and downs in vulnerability to addictions: a neurodevelopmental model. Trends Pharmacol Sci 35: 268-276. doi: 10.1016/j.tips.2014.04.002
    [28] Oberlin BG, Dzemidzic M, Tran SM, et al. (2013) Beer flavor provokes striatal dopamine release in male drinkers: mediation by family history of alcoholism. Neuropsychopharmacology 38: 1617-1624. doi: 10.1038/npp.2013.91
    [29] Blum K, Gondré-Lewis MC, Baron D, et al. (2018) Introducing Precision Addiction Management of Reward Deficiency Syndrome, the Construct That Underpins All Addictive Behaviors. Front Psychiatry 9: 548. doi: 10.3389/fpsyt.2018.00548
    [30] Li TK, Bosron WF (1986) Genetic variability of enzymes of alcohol metabolism in human beings. Ann Emerg Med 15: 997-1004. doi: 10.1016/S0196-0644(86)80118-4
    [31] Setshedi M, Wands JR, Monte SM (2010) Acetaldehyde adducts in alcoholic liver disease. Oxid Med Cell Longev 3: 178-185. doi: 10.4161/oxim.3.3.12288
    [32] Vaswani M (2019) . ADH and ALDH Polymorphisms in Alcoholism and Alcohol Misuse/Dependence Academic Press, 29-38.
    [33] Peng GS, Yin SJ (2009) Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations. Hum Genomics 3: 121-127. doi: 10.1186/1479-7364-3-2-121
    [34] Sanchez-Roige S, Palmer AA, Clarke TK (2020) Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse. Biol Psychiatry 87: 609-618. doi: 10.1016/j.biopsych.2019.09.011
    [35] Zhong Y, Dong G, Luo H, et al. (2012) Induction of brain CYP2E1 by chronic ethanol treatment and related oxidative stress in hippocampus, cerebellum, and brainstem. Toxicology 302: 275-284. doi: 10.1016/j.tox.2012.08.009
    [36] Chapter 25: Metabolism of Ethanol. Semantic Scholar .
    [37] Larson HN, Weiner H, Hurley TD (2005) Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase “Asian” variant. J Biol Chem 280: 30550-30556. doi: 10.1074/jbc.M502345200
    [38] Santoro N, Zhang CK, Zhao H, et al. (2012) Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55: 781-789. doi: 10.1002/hep.24806
    [39] Ng E, Lind PM, Lindgren C, et al. (2015) Genome-wide association study of toxic metals and trace elements reveals novel associations. Hum Mol Genet 24: 4739-4745. doi: 10.1093/hmg/ddv190
    [40] Bishehsari F, Magno E, Swanson G, et al. (2017) Alcohol and Gut-Derived Inflammation. Alcohol Res 38: 163-171.
    [41] Hubacek JA, Adamkova V, Dlouha D, et al. (2012) Fat mass and obesity-associated (FTO) gene and alcohol intake. Addiction 107: 1185-1186. doi: 10.1111/j.1360-0443.2012.03825.x
    [42] Antonio J, Knafo S, Kenyon M, et al. (2019) Assessment of the FTO gene polymorphisms (rs1421085, rs17817449 and rs9939609) in exercise-trained men and women: the effects of a 4-week hypocaloric diet. J Int Soc Sports Nutr 16: 36. doi: 10.1186/s12970-019-0307-6
    [43] Zhou H, Sealock JM, Sanchez-Roige S, et al. (2020) Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits. Nat Neurosci 23: 809-818. doi: 10.1038/s41593-020-0643-5
    [44] Ramchandani VA, Umhau J, Pavon FJ, et al. (2011) A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry 16: 809-817. doi: 10.1038/mp.2010.56
    [45] Rinker JA, Fulmer DB, Trantham-Davidson H, et al. (2017) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol 58: 33-45. doi: 10.1016/j.alcohol.2016.05.007
    [46] Koyama S, Brodie MS, Appel SB (2007) Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. J Neurophysiol 97: 1977-1985. doi: 10.1152/jn.00270.2006
    [47] Kendler KS, Kalsi G, Holmans PA, et al. (2011) Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcohol Clin Exp Res 35: 963-975. doi: 10.1111/j.1530-0277.2010.01427.x
    [48] Hamilton PJ, Nestler EJ (2019) Epigenetics and addiction. Curr Opin Neurobiol 59: 128-136. doi: 10.1016/j.conb.2019.05.005
    [49] Przybycien-Szymanska MM, Rao YS, Prins SA, et al. (2014) Parental binge alcohol abuse alters F1 generation hypothalamic gene expression in the absence of direct fetal alcohol exposure. PLoS One 9: e89320. doi: 10.1371/journal.pone.0089320
    [50] Mark TL, Kassed CA, Vandivort-Warren R, et al. (2009) Alcohol and opioid dependence medications: prescription trends, overall and by physician specialty. Drug Alcohol Depend 99: 345-349. doi: 10.1016/j.drugalcdep.2008.07.018
    [51] Medications Development Program National Institute on Alcohol Abuse and Alcoholism: U.S. Department of Health and Human Services (2019) .
    [52] Keung WM, Vallee BL (1993) Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase. Proc Natl Acad Sci U S A 90: 1247-1251. doi: 10.1073/pnas.90.4.1247
    [53] Kushner S, Han D, Oscar-Berman M, et al. (2013) Declinol, a Complex Containing Kudzu, Bitter Herbs (Gentian, Tangerine Peel) and Bupleurum, Significantly Reduced Alcohol Use Disorders Identification Test (AUDIT) Scores in Moderate to Heavy Drinkers: A Pilot Study. J Addict Res Ther 4. doi: 10.4172/2155-6105.1000153
    [54] Arolfo MP, Overstreet DH, Yao L, et al. (2009) Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcohol Clin Exp Res 33: 1935-1944. doi: 10.1111/j.1530-0277.2009.01031.x
    [55] Chick J (1999) Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf 20: 427-435. doi: 10.2165/00002018-199920050-00003
    [56] Spanagel R, Vengeliene V, Jandeleit B, et al. (2014) Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology 39: 783-791. doi: 10.1038/npp.2013.264
    [57] De Witte P, Littleton J, Parot P, et al. (2005) Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 19: 517-537. doi: 10.2165/00023210-200519060-00004
    [58] Ding ZM, Rodd ZA, Engleman EA, et al. (2013) Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol-preferring (P) rats. Addict Biol 18: 297-306. doi: 10.1111/adb.12018
    [59] Saellstroem Baum S, Huebner A, Krimphove M, et al. (2006) Nicotine stimulation on extracellular glutamate levels in the nucleus accumbens of ethanol-withdrawn rats in vivo. Alcohol Clin Exp Res 30: 1414-1421. doi: 10.1111/j.1530-0277.2006.00169.x
    [60] Umhau JC, Momenan R, Schwandt ML, et al. (2010) Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67: 1069-1077. doi: 10.1001/archgenpsychiatry.2010.125
    [61] Koob GF, Mason BJ, De Witte P, et al. (2002) Potential neuroprotective effects of acamprosate. Alcohol Clin Exp Res 26: 586-592. doi: 10.1111/j.1530-0277.2002.tb02578.x
    [62] Maisel NC, Blodgett JC, Wilbourne PL, et al. (2013) Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction 108: 275-293. doi: 10.1111/j.1360-0443.2012.04054.x
    [63] Naltrexone Medication-Assisted Treatment: Substance Abuse and Mental Health Services Administration (2020) .
    [64] Biernacka JM, Coombes BJ, Batzler A, et al. (2021) Genetic Contributions to Alcohol Use Disorder Treatment Outcomes: A Genome-wide Pharmacogenomics Study. Neuropsychopharmacology .
    [65] Gunthorpe MJ, Large CH, Sankar R (2012) The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia 53: 412-424. doi: 10.1111/j.1528-1167.2011.03365.x
    [66] Li Y, Li Q, Li W, et al. (2019) The polymorphism of dopamine D2 receptor TaqIA gene is associated with brain response to drug cues in male heroin-dependent individuals during methadone maintenance treatment. Drug Alcohol Depend 198: 150-157. doi: 10.1016/j.drugalcdep.2019.01.028
    [67] Kroslak T, Laforge KS, Gianotti RJ, et al. (2007) The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J Neurochem 103: 77-87.
    [68] Ritchie T, Noble EP (2003) Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 28: 73-82. doi: 10.1023/A:1021648128758
    [69] Anghelescu I, Germeyer S, Müller MJ, et al. (2001) No association between the dopamine d2 receptor taqi a1 allele and earlier age of onset of alcohol dependence according to different specified criteria. Alcohol Clin Exp Res 25: 805-809. doi: 10.1111/j.1530-0277.2001.tb02283.x
    [70] Berggren U, Fahlke C, Aronsson E, et al. (2006) The taqI DRD2 A1 allele is associated with alcohol-dependence although its effect size is small. Alcohol Alcohol 41: 479-485. doi: 10.1093/alcalc/agl043
    [71] Wang F, Simen A, Arias A, et al. (2013) A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence. Hum Genet 132: 347-358. doi: 10.1007/s00439-012-1251-6
    [72] Lee SH, Lee BH, Lee JS, et al. (2013) The association of DRD2 -141C and ANKK1 TaqIA polymorphisms with alcohol dependence in Korean population classified by the Lesch typology. Alcohol Alcohol 48: 426-432. doi: 10.1093/alcalc/agt029
    [73] Dahlgren A, Wargelius HL, Berglund KJ, et al. (2011) Do alcohol-dependent individuals with DRD2 A1 allele have an increased risk of relapse? A pilot study. Alcohol Alcohol 46: 509-513. doi: 10.1093/alcalc/agr045
    [74] Bond C, LaForge KS, Tian M, et al. (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 95: 9608-9613. doi: 10.1073/pnas.95.16.9608
    [75] Mahmoud S, Thorsell A, Sommer WH, et al. (2011) Pharmacological consequence of the A118G µ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca2+ channels in humanized mouse sensory neurons. Anesthesiology 115: 1054-1062. doi: 10.1097/ALN.0b013e318231fc11
    [76] Oertel BG, Kettner M, Scholich K, et al. (2009) A common human micro-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J Biol Chem 284: 6530-6535. doi: 10.1074/jbc.M807030200
    [77] Taqi MM, Faisal M, Zaman H (2019) OPRM1 A118G Polymorphisms and Its Role in Opioid Addiction: Implication on Severity and Treatment Approaches. Pharmgenomics Pers Med 12: 361-368.
    [78] Sadee W, Hartmann K, Seweryn M, et al. (2014) Missing heritability of common diseases and treatments outside the protein-coding exome. Hum Genet 133: 1199-1215. doi: 10.1007/s00439-014-1476-7
    [79] Nam HW, Karpyak VM, Hinton DJ, et al. (2015) Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects. Transl Psychiatry 5: e621. doi: 10.1038/tp.2015.120
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