Genetic pre-determinants of concurrent alcohol and opioid dependence : A critical review

Title Genetic pre-determinants of concurrent alcohol and opioid dependence: a critical review Authors(s) Martin, Marissa; Klimas, Jan; Dunne, Colum; Meagher, David; O'Connor, William T.; O'Dwyer, Patrick; Smyth, Bobby P.; Cullen, Walter Publication date 2013-11 Publication information Open Access Alcohol, 1 (2): 18 Publisher OA Publishing London Link to online version https://www.oapublishinglondon.com/article/978 Item record/more information http://hdl.handle.net/10197/5486


Introduction
Problem of opioid use is highly prevalent in Europe, including high rates in Ireland of seven per 1000 persons 1 .Opioids are responsible for the highest rate of drug-related morbidity and mortality, contributing to greater than 77% of drug-induced fatalities in Europe 1 .Concurrent alcohol dependence poses a significant burden to the healthcare of people with established opioid dependence 2 .Its negative impacts on addiction treatment include behaviours leading to clinical management difficulties, e.g.illicit drug use or non-adherence with clinicians' advice and early dropout 3 .
Multiple studies have confirmed that both gene-gene and gene-environment interactions contribute to the development of drug dependence or alcohol dependence alone 4 .Alcohol dependence has been associated with polymorphisms in genes coding for opioid receptors, serotonin receptors, GABA-ergic receptors, nicotinic and muscarinic acetylcholine receptors, CREB genes involved in familial predisposition to alcohol (cyclic AMP responsive element binding protein) and alcohol dehydrogenase (ADH) 5 .Opioid dependence has been associated with opioid system genes, particularly the mu-opioid receptor gene PKNOX2, as well as the dopaminergic system 6 .Genome-wide association studies of multiple addictions have discussed potential vulnerability genes, more specifically cell adhesion genes that control the formation, stabilisation, enhancement and elimination of contacts between brain cells 7 .A previous review has discussed several genes associated with multiple addictions; however, the contribution of genes to concurrent alcohol and opioid dependence has been neglected to date 4 .
Clinical experience suggests that alcohol and opioid dependence may have common genetic aetiological origin.For example, Naltrexone (an opiate antagonist) is useful in the treatment of alcohol dependence 8 .Most psychotropic substances (apart from benzodiazepines) have been shown to directly or indirectly increase dopaminergic activity in the "reward pathway" (nucleus accumbans-ventral tegmental area-pre frontal cortex) 1 .Alcohol and opiates stimulate the mu-opioid receptor on the GABA neuron, thereby inhibiting its activity in GABA.This, in turn, reduces the inhibitory effect of GABA on the dopaminergic system in nucleus accumbans and the prefrontal cortex.Studies have found elevations of mu-opioid receptors in people with alcohol dependence 9 .Higher observed rates of alcohol dependence in parents of adults with heroin dependence raise the possibility of a common risk factor.Another clinical reality is that early onset drinking may be associated with subsequent heroin dependence.Alcohol dependence in this cohort tends to become evident only after entry into opioid substitution treatment, following cessation or dramatic reduction in heroin use 10 .Taken together, clinical evidence suggests the possibility of a common genetic link between opioid and alcohol dependence but the nature of that link remains unclear.
The aim of the present paper was to critically review genetic pre-determinants of concurrent alcohol and opioid dependence through an electronic search of the relevant literature.Electronic searches were completed using MEDLINE (PubMed) and EBSCO (academic search complete) databases.

Discussion
The authors have referenced some of their own studies in this review.These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed.All human subjects, in these referenced studies, gave informed consent to participate in these studies.
Twenty included studies examined the role of 33 genes in alcohol or opioid dependence.They were associated with the opioid, cholinergic, serotonergic, dopaminergic, GABAergic, cannabinoid and metabolic systems.The identified genes classified by their system and function are presented in Table 1.

Opioid system
Seven studies investigated the role of genes in the opioid system [11][12][13][14][15][16][17][18] .Genes encoding all three types of opioid receptors were studied with variable results.Kumar et al. and Deb et al.  concluded that the A118G polymorphism of OPRM1 (mu-opioid receptor gene) was associated with alcohol and opioid addiction in males in Eastern India 16,17 .Kumar et al. found that people with alcohol dependence and heroin dependence were 1.7 times and 1.9 times more likely, respectively, than control subjects to have the A11G polymorphism 16 .Deb et al. found that subjects with alcohol dependence and opioid dependence were more likely than control to have the A11G polymorphism 17 .However, a study conducted in Germany by Franke et al. found no difference in the frequency of the A118G polymorphism between heroin or alcohol dependent subjects and controls 15 .In addition to the A118G single nucleotide polymorphism (SNP), Luo et al. found that the allele -2442A of OPRM1 was associated with concurrent alcohol and opioid dependence in European Americans, but not in African Americans 13 .
Zhang et al. conducted the only apparent study to associate the delta opioid receptor gene (OPRD1) with alcohol and opioid addiction.They found that the GCAACT haplotype containing G80T G-allele and C921T C-allele was associated with an increased risk of alcohol dependence (OR = 6.43) and opioid addiction (OR = 50.57) 11.Franke et al. studied the silent T to C substitution at position 921 and found no association between this polymorphism and alcohol or opioid addiction 14 .Similarly, Xuei et al. used a family-based association to investigate the opioid system in alcohol and drug dependence by analysing the genes encoding the micro-and delta-opioid receptors and their peptide ligands.They found no significant associations of the OPRM1, OPRD1, PENK and POMC genes with alcohol or illicit drug dependence 18 .In summary, the results of opioid receptors are variable with OPRMI being most promising.

Dopaminergic system
A study by Yang et al. analysed the cluster of genes functionally associated with the dopaminergic system on chromosome 11q23.These genes included DRD2, TTC12, ANKK1 and NCAM1.They concluded that variants in TTC12 exon 3, NCAM1 exon 12 and the two 3¢-ends of ANKK1 and DRD2 co-regulate risk for concurrent alcohol dependence and drug dependence 19 .This co-regulation may play a role in concurrent dependencies, but we found only one study with such result.ADH A total of seven ADH genes (ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6 and ADH7) were analysed in two separate studies 20,21 .It is important to note that this was a recessive association.Two ADH4 SNPs (rs1042363 and rs1800759) showed Hardy-Weinberg disequilibrium in Americans of European origin but not in controls 20 .Two SNPs were more likely to be associated with concurrent drug and alcohol dependence in European Americans (ADH5 rs1154400 and ADH7 rs1573496), compared to drug dependence alone 21 .One SNP was associated with concurrent drug and alcohol dependence in African Americans (ADH1C rs1693482) and one SNP was associated with concurrent drug and alcohol dependence in both populations (ADH1B rs1229984) 21 .It seems that the ADH genes function in concurrent dependencies is population-specific.

Cholinergic
Genes for both muscarinic and nicotinic cholinergic receptors play a significant role in concurrent alcohol and opioid dependence 22,23 .Dick et al. found 11 SNPs of muscarinic acetylcholine receptor gene (CHRM2) to be significant for individuals with alcohol dependence and concurrent drug dependence.These SNPs were not found to be associated with alcohol dependence alone 22 .Sherva et al. investigated the role of the nicotinic gene cluster on chromosome 15q25.1 in case-control and familybased association studies.They found that multiple SNPs were associated with substance dependence, but only one SNP (rs16969968) was associated with both alcohol dependence and opioid dependence 23 .

Serotonergic
Two studies have examined the role of the serotonergic system 24,25 focusing on the 5HT-transporter gene, SLC 6A4.Saiz et al. found no significant differences in the genotypic frequencies of the 5-HTTLPR and STin2 VNTR polymorphisms of SLC 6A4 between subjects with heroin addiction, alcohol addiction or controls.This study also did not find an association between HTR2A A-1438G polymorphism and alcohol or opioid addiction 25 .Enoch et al.
found that low 5-HTTLPR activity and the HTR2B Ser 129 allele were more common in men with concurrent alcohol and drug dependence compared with controls.Together, they had an additive effect.The study also found no association between HTR3A haplotype and alcohol or drug dependence 24 .Serotogenic system appears to be less important for concurrent dependencies.

GABA-ergic
Three studies investigated the role of GABA-receptor genes in substance dependence [26][27][28]  A family-based association study conducted by Agrawal et al. found an association between five GABRA2 SNPs and concurrent alcohol and drug dependence.No association was found with any other GABAA receptor genes (GABRA2, GABRA4, GABRB1 and GBRG2) 27 .On the whole, some GABA-ergic genes can be relevant for concurrent dependencies, but no GABAA receptor genes.

IL-B
A case-control study from Australia found that IL-1B, IL-511C and IL-31T alleles were more frequent in both opioid-and alcohol-dependent patients compared with controls 29 .While the higher frequency of these alleles in both dependencies may suggest a link with concurrent dependencies, only one study showed such results.

Nociception
Xuei et al. conducted a study on the role of the nociception receptor gene (OPRL1) and its ligand (PNOC) on substance dependence in European Americans.SNPs in PNOC showed marginal association with alcohol dependence rs17058952 (p = 0.05).Two adjacent SNPs in intron 1 of OPRL1 were marginally associated with opioid dependence [rs6512305 (p = 0.05) and rs6090043 (p = 0.05)].However, neither gene showed association with both alcohol and opioid dependence 12 .

Cannabinoid
A study conducted by Zuo et al. found that for European Americans, the risk for developing substance dependence significantly increased with the number of 'G' alleles at rs6454674 in the cannabinoid receptor gene (CNR1).Interaction between rs6454674 and rs806368 had a significant risk factor for alcohol dependence, drug dependence cocaine and/or alcohol dependence and concurrent alcohol and drug dependence 30 .

Future research
Some evidence suggests that muscarinic CHRM2 may be implicated in concurrent alcohol and opioid dependence; similarly, dopaminergic mechanisms are very likely to be relevant to both dependencies.Like most conditions, none of those genes can be identified as their sole genetic pre-determinant.The impact of genes on concurrent dependence results at least in part from the combined effects of multiple genes 4 .
Many other addictions also commonly coexist with opioid dependence, e.g.cannabis, benzodiazepines or tobacco 4 .Current neurobiological theories of addiction suggest that people with hypoactivity of dopamine system may be more vulnerable to developing all addictions 4 .Also, current theory on mechanism of addiction centres on impairment of ability of pre-frontal cortex to inhibit hedonic activity, i.e. past drug use damages the brain's 'braking' system, making it harder to resist impulse to use again in future 9 .Therefore, if one has a genetically caused dopaminergic hypo-activity or a prefrontal cortex more prone (genetically) to damage by past addiction to other substance, one may be more likely to develop any other addiction.Hence, if there are genes that are associated with increased risk of alcohol dependence in people who are dependent on opioids, some of these genes may cause a specific increase in risk of alcohol dependence, while others may just cause a general increase in all other addictions, including alcohol.
Multiple studies confirmed that both gene-gene and gene-environment interactions contribute to the development of drug dependence or alcohol dependence 4 .This is consistent with the notion that no condition should be studied in isolation.Gene expression is as important as gene-environment interaction and individual upbringing or personality, all of which influence dependence.Therefore, a systematic review on the relationships between genes and environment (including social and/ or psychological sequel) is needed to provide context necessary for identification of genetic pre-determinants of a concurrent dependence.
Many studies were conducted by the same group of researchers; they studied cohorts of European-Americans and African-American subpopulations 11,13,19,23,30 .None of those studies were performed in Ireland or the United Kingdom.This omission provides an opportunity for further exploration in these countries.Ireland is located on the Western edge of Europe and may have a different gene pool compared with the rest of Europe.Additionally, Ireland has the third highest per capita alcohol consumption in Europe as well as the highest rate of binge drinking 1 .Moreover, such observation underscores the need to carefully identify the ethnic origins of each sub-population, as the prevalence of a given polymorphism can vary across populations.For example, the prevalence of the A118G variant of the mu-opioid receptor gene varies from 2% to 49% among different ethnic groups 31 .Asian 'glow' is yet another well recognised example of how ethnicity can impact upon genetic expression that is relevant to alcohol use.These polymorphisms may account for the varying results among European, African American or Asian studies.
It is also likely that the genes responsible for addictive disorders are present in a much greater percentage of the population than the phenotype due to a limited availability of illicit substances such as opioids.For future case-control studies, we suggest that the control groups should consist of people with opioid dependencies who were nondependent alcohol drinkers.From a clinical perspective, the issue of dual dependence tends to be a concern in one direction only.Treatment providers do not encounter a substantial number of people with alcohol dependence going on to become opioid dependent.Only a minority of patients treated for alcohol dependence ever use illicit opioids.One could speculate that while they may have high-risk gene for development of opioid dependence this risk never becomes manifest in the absence of use of that class of drugs.However, almost everyone who is opioid dependent will have had exposure to alcohol use.Hence, if they had a risky gene, it would be quite likely to manifest itself.
Finally, we suggest that examining the genetic pre-determinants feature prominently in future research endeavours among problem drug users, especially in geographical regions with a high prevalence of concurrent alcohol and opioid dependency.

Conclusion
On the basis of the electronic search of relevant literature, the current evidence base is inconclusive regarding an exclusively genetic predeterminant of concurrent alcohol and opioid dependence.A systematic review of literature is needed; however, our findings do have some immediate implications for trial design.Trials should use precise and consistent criteria for selection of subjects with dual drug dependence.Future case-control studies should have control groups that consist of people with opioid dependencies who are non-dependent problem alcohol users.Future investigations of the genetic pre-determinants of these concurrent problems should focus on high-risk populations and regions.