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Levran O.,Rockefeller University | Randesi M.,Rockefeller University | Peles E.,Dr Miriam And Sheldon G Adelson Clinic For Drug Abuse Treatment And Research | Peles E.,Tel Aviv University | And 7 more authors.
Pharmacogenomics | Year: 2016

Aim: This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence. Patients & methods: The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed. Results: Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1. Conclusion: Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers. © 2016 Future Medicine Ltd. Source


Levran O.,Rockefeller University | Peles E.,Dr Miriam And Sheldon G Adelson Clinic For Drug Abuse Treatment And Research | Peles E.,Tel Aviv University | Randesi M.,Rockefeller University | And 7 more authors.
Pharmacogenomics | Year: 2014

Background & aim: The dopaminergic pathways have been implicated in the etiology of drug addictions. The aim of this study was to determine if variants in dopaminergic genes are associated with heroin addiction. Materials & methods: The study includes 828 former heroin addicts and 232 healthy controls, of predominantly European ancestry. Ninety seven SNPs (13 genes) were analyzed. Results: Nine nominally significant associations were observed at CSNK1E, ANKK1, DRD2 and DRD3. Conclusion: The results support our previous report of association of CSNK1E SNP rs1534891 with protection from heroin addiction. CSNK1E interacts with circadian rhythms and DARPP-32 and has been implicated in negative regulation of sensitivity to opioids in rodents. It may be a target for drug addiction treatment. Original submitted 8 August 2014; Revision submitted 8 October 201. © 2014 Future Medicine Ltd. Source


Levran O.,Rockefeller University | Peles E.,Dr Miriam And Sheldon G Adelson Clinic For Drug Abuse Treatment And Research | Peles E.,Tel Aviv University | Randesi M.,Rockefeller University | And 7 more authors.
Psychoneuroendocrinology | Year: 2014

Background: Stress 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. Methods: 112 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. Results: Nineteen 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. Conclusions: This 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. © 2014 Elsevier Ltd. Source


Levran O.,Rockefeller University | Peles E.,Dr Miriam And Sheldon G Adelson Clinic For Drug Abuse Treatment And Research | Peles E.,Tel Aviv University | Randesi M.,Rockefeller University | And 7 more authors.
CNS Neuroscience and Therapeutics | Year: 2015

Aim: 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. Methods: Analyses were conducted in a sample of 1860 subjects divided according to ancestry (African and European) and drug of abuse (heroin or cocaine). Results: Eighteen SNPs in 11 genes (CDK5R1, EPHA4, EPHA6, FOSL2, MAPK3, MBP, MPDZ, NFKB1, NTRK2, NTSR1, and PRKCE) showed significant associations (P < 0.01), but the signals did not survive correction for multiple testing. SNP rs230530 in the NFKB1 gene, encoding the transcription regulator NF-kappa-B, was the only SNP indicated in both ancestry groups and both addictions. This SNP was previously identified in association with alcohol addiction. SNP rs3915568 in NTSR1, which encodes neurotensin receptor, and SNP rs1389752 in MPDZ, which encodes the multiple PDZ domain protein, were previously associated with heroin addiction or alcohol addiction, respectively. Conclusions: The study supports the involvement of genetic variation in signal transduction pathways in heroin and cocaine addiction and provides preliminary evidence suggesting several new risk or protective loci that may be relevant for diagnosis and treatment success. © 2015 John Wiley & Sons Ltd. Source


Levran O.,Rockefeller University | Peles E.,Dr Miriam And Sheldon G Adelson Clinic For Drug Abuse Treatment And Research | Randesi M.,Rockefeller University | Shu X.,University of Michigan | And 5 more authors.
Pharmacogenomics | Year: 2013

Aim: The interindividual variability in the dose required for effective methadone maintenance treatment (MMT) for opioid addiction may be influenced in part by genetic variations in genes encoding pharmacodynamic factors of methadone. This study was conducted to identify some of these variants. Materials & methods: This study focused on 11 genes encoding components of the opioidergic (OPRM1, POMC and ARRB2), the dopaminergic (ANKK1 and DRD2) and the glutamatergic pathways (GRIN1 and GRIN2A), as well as the neurotrophin system (NGFB, BDNF, NTRK1 and NTRK2). The study includes 227 Israeli patients undergoing stable MMT. Results: Out of the 110 variants analyzed, 12 SNPs (in BDNF, NTRK2, OPRM1, DRD2 and ANKK1) were associated with methadone dose (nominal p < 0.05). Of these SNPs, ANKK1 rs7118900 and DRD2 rs2283265 are known to affect gene expression. Logistic regression of five representative SNPs discriminated between individuals requiring a methadone dose of >120 mg/day and <120 mg/day (p = 0.019), and showed moderate sensitivity and specificity (AUC of 0.63 in receiver operating characteristic analysis). Conclusion: This data should stimulate further research on the potential influence and clinical significance of these variants on MMT. Original submitted 14 November 2012; Revision submitted 12 March 201. © 2013 Future Medicine Ltd. Source

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