Miriam Adelson

Genetic susceptibility to heroin addiction: a candidate gene association study

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (Pu2003<u20030.01). These variants were in noncoding regions of the genes encoding the mu (OPRM1; rs510769 and rs3778151), kappa (OPRK1; rs6473797) and delta (OPRD1; rs2236861, rs2236857 and rs3766951) opioid receptors; the neuropeptide galanin (GAL; rs694066); the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multilocus genotype patterns showed nominally significant associations (e.g. OPRM1; Pu2003=u20030.0006 and CSNK1E; Pu2003=u20030.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (Pu2003=u20030.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction, which is worthy of future study.

Characteristics of benzodiazepine abuse in methadone maintenance treatment patients: a 1 year prospective study in an Israeli clinic

We aimed to study the prevalence patterns and course of benzodiazepine (BZD) abuse in an Israeli methadone maintenance (MMT) clinic using repeated random observed urine analysis as well as self-report data. Lifetime and current prevalence of BZD abuse were found in 66.3 and 50.8% patients, respectively. It was found that 44.6% of patients who abused BZDs during their first month of treatment ceased to do so after 1 year, while 27.4% who had not abused BZDs at the beginning of MMT did so after 1 year in treatment. Flunitrazepam was the most commonly abused BZD (92.9%), followed by diazepam (54.3%) and oxazepam (38.6%). Most of the patients swallowed BZDs (92.8%), 42.9% also smoked or snorted them while 8.6% injected BZDs intravenously. BZDs were used as self-medication for alleviating emotional problems rather than for recreational or other reasons. We conclude that BZD abuse is a significant clinical problem in heroin addicts both before entering and during MMT. MMT may have a positive as well as a negative influence on BZD abuse with the former being more prevalent.

Stress-related genes and heroin addiction: A role for a functional FKBP5 haplotype

BACKGROUNDnStress is a critical risk factor affecting both the development of and the relapse to drug addictions. Drug addictions are caused by genetic, environmental and drug-induced factors. The objective of this hypothesis-driven association study was to determine if genetic variants in stress-related genes are associated with heroin addiction.nnnMETHODSn112 selected genetic variants in 26 stress-related genes were genotyped in 852 case subjects and 238 controls of predominantly European ancestry. The case subjects are former heroin addicts with a history of at least one year of daily multiple uses of heroin, treated at a methadone maintenance treatment program (MMTP). The two most promising SNPs were subsequently tested in an African-American sample comprising of 314 cases and 208 control individuals.nnnRESULTSnNineteen single nucleotide polymorphisms (SNPs) in 9 genes (AVP, AVPR1A, CRHR1, CRHR2, FKBP5, GAL, GLRA1, NPY1R and NR3C2) showed nominally significant association with heroin addiction. The associations of two FKBP5 SNPs that are part of one haplotype block, rs1360780 (intron 2) and rs3800373 (the 3 untranslated region), remained significant after correction for multiple testing (Pcorrected=0.03; OR=2.35, Pcorrected=0.0018; OR=2.85, respectively). The two SNPs also showed nominally significant association (P<0.05) with heroin addiction in an independent African-American cohort. FKBP5 is a co-chaperone that regulates glucocorticoid sensitivity. These FKBP5 SNPs were previously associated with diverse affective disorders and showed functional differences in gene expression and stress response. This study also supports our and others previous reports of association of the GAL SNP rs694066 and the AVPR1A SNPs rs11174811, rs1587097 and rs10784339 with heroin and general drug addiction, respectively.nnnCONCLUSIONSnThis study suggests that variations in the FKBP5 gene contribute to the development of opiate addiction by modulating the stress response. These findings may enhance the understanding of the interaction between stress and heroin addiction.

Drug Addiction and Stress-Response Genetic Variability: Association Study in African Americans

Stress is a significant risk factor in the development of drug addictions and in addiction relapse susceptibility. This hypothesis‐driven study was designed to determine if specific SNPs in genes related to stress response are associated with heroin and/or cocaine addiction in African Americans. The analysis included 27 genes (124 SNPs) and was performed independently for each addiction. The sample consisted of former heroin addicts in methadone maintenance treatment (n = 314), cocaine addicts (n = 281), and controls (n = 208). Fourteen SNPs showed nominally significant association with heroin addiction (p < 0.05), including the African‐specific, missense SNP rs5376 (Asn334Ser) in the galanin receptor type 1 gene (GALR1) and the functional FKBP5 intronic SNP rs1360780. Thirteen SNPs showed association with cocaine addiction, including the synonymous SNPs rs237902, in the oxytocin receptor gene (OXTR), and rs5374 in GALR1. No signal remained significant after correction for multiple testing. Four additional SNPs (GALR1 rs2717162, AVP rs2282018, CRHBP rs1875999, and NR3C2 rs1040288) were associated with both addictions and may indicate common liability. The study provides preliminary evidence for novel association of variants in several stress‐related genes with heroin and/or cocaine addictions and may enhance the understanding of the interaction between stress and addictions.

Overlapping Dopaminergic Pathway Genetic Susceptibility to Heroin and Cocaine Addictions in African Americans

Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine‐related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single‐marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7‐SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent.

Synaptic Plasticity and Signal Transduction Gene Polymorphisms and Vulnerability to Drug Addictions in Populations of European or African Ancestry.

Drug addiction is characterized, in part, by deregulation of synaptic plasticity in circuits involved in reward, stress, cue learning, and memory. This study was designed to assess whether 185 variants in 32 genes central to synaptic plasticity and signal transduction contribute to vulnerability to develop heroin and/or cocaine addiction.

Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry

BACKGROUNDnDrug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction.nnnMETHODSnFour independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European).nnnRESULTSnA total of 11 SNPs in eight genes showed nominally significant associations (P<0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes.nnnCONCLUSIONSnThe study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction.

The μ-opioid receptor nonsynonymous variant 118A>G is associated with prolonged abstinence from heroin without agonist treatment

AIMnThis study assesses whether opioid-related gene variants contribute to reduced vulnerability to relapse to heroin in persons who are not treated with μ-opioid receptor agonist.nnnMETHODSnGenotypes of 71xa0SNPs, in nine genes, were analyzed for association with long-term abstinence in former heroin-dependents of European/Middle Eastern ancestry, either without agonist treatment (nxa0=xa0129) or in methadone maintenance treatment (nxa0=xa0922).nnnRESULTSnThe functional OPRM1 nonsynonymous SNP rs1799971 (118A>G) showed significant association with long-term abstinence (Ppermutation xa0=xa00.03, dominant model, OR: 2.2; 95% CI: 1.5-3.3).nnnCONCLUSIONnSince the stress axis is regulated in part by β-endorphin, this functional OPRM1 SNP may blunt the endogenous stress response and contribute to reduced vulnerability for relapse.

A naturalistic study on ending blind dosing in a methadone maintenance clinic in Israel

Since many methadone maintenance treatment (MMT) clinics in the United States do not share with patients, information concerning their methadone dosage, we aimed to investigate the impact of patients being informed of their methadone dosage and the influence of ending blind dosing on treatment outcome. Seventy-four patients who were unaware of their methadone dosage took part in this study. We compared changes in opiate abuse, levels of methadone dosage and patients perceptions of dosage adequacy before and after they were informed of their dosage. Data on opiate abuse were based upon bi-weekly randomly taken and observed urine tests provided the data on opiate abuse. Records on methadone dosage were kept and a short questionnaire on dosage-related attitudes, devised for this study, was administered. Most patients expressed the desire to know their dosage, but there were no significant changes in opiate abuse, methadone dosage or the patients perceptions of dosage adequacy after they knew what it was. We conclude that informing patients of their methadone dosage and thereby ending blind dosing does not seem to have any negative effect on treatment outcomes. We believe that this policy is in accord with the patients rights and expressed will to know their dosage and this justifies putting an end to blind dosing policies.