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1.
Mol Psychiatry ; 26(7): 3169-3177, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33037305

RESUMEN

The mu-opioid receptor (MOR, OPRM1) has important roles in diverse functions including reward, addiction, and response to pain treatment. SNP rs1799971 (118A > G, N40D) which occur at a high frequency (40-60%) in Asia and moderate frequency (15%) in samples of European ancestry, is the only common coding variant in the canonical transcript, in non-African populations. Despite extensive studies, the molecular consequences of this variation remained unresolved. The aim of this study was to determine the genetic background of the OPRM1 region of 118G in four representative populations and to assess its potential modulatory effect. Seven common haplotypes with distinct population distribution were identified based on seven SNPs. Three haplotypes carry the 118G and additional highly linked regulatory SNPs (e.g., rs9383689) that could modulate the effect of 118G. Extended analysis in the 1000 Genomes database (n = 2504) revealed a common East Asian-specific haplotype with a different genetic background in which there are no variant alleles for an upstream LD block tagged by the eQTL rs9397171. The major European haplotype specifically includes the eQTL intronic SNP rs62436463 that must have arisen after the split between European and Asian populations. Differentiating between the effect of 118G and these SNPs requires specific experimental approaches. The analysis also revealed a significant increase in two 118A haplotypes with eQTL SNPs associated with drug addiction (rs510769) and obesity (rs9478496) in populations with native Mexican ancestry. Future studies are required to assess the clinical implication of these findings.


Asunto(s)
Genética de Población , Medicina Genómica , Receptores Opioides mu , Alelos , Antecedentes Genéticos , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Receptores Opioides mu/genética
2.
Eur Addict Res ; 27(3): 198-205, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33242852

RESUMEN

BACKGROUND: As CRH-binding protein (CRHBP) SNP rs1500 was associated with reduced cocaine abuse after 1 year in methadone maintenance treatment (MMT) for heroin addiction, we evaluated the association of additional 28 selected SNPs, in 17 stress-related genes, with MMT outcome. METHODS: The distribution of genotypes of each SNP by cocaine abuse after 1 year in MMT was assessed under the dominant and recessive models using χ2. Cumulative retention (up to 26.5 years) was studied using Kaplan-Meier analyses. Logistic regression and Cox model were used for multivariate analyses. RESULTS: Of a nonselective sample of 404 patients, 25 patients with <50% Europeans/Middle Eastern ancestry were excluded. Of the remaining 379 patients, 330 (87.1%) stayed at least 1 year in treatment. Four SNPs were associated with cocaine abuse after 1 year in MMT. A lower proportion of cocaine abusers was found in the groups of subjects with the following genotypes: arginine vasopressin (AVP) SNP rs2282018 CC, CRHBP rs7728378 TT, galanin rs3136541 TT/TC, and neuropeptide Y receptor Y1 (NPY1R) rs4518200 AA. The following independent variables were associated with lack of cocaine in urine after 1 year (multivariate analyses): CRHBP rs7728378 TT, NPY1R rs4518200 AA, no cocaine in urine on admission, as well as opiate and benzodiazepine use after 1 year in MMT. Cumulative retention (n = 379) was longer in carriers of AVP rs2282018 CC (13.7 years, 95% CI 11.1-16.2) versus TT/TC genotypes (10.5, 95% CI 9.4-11.5) (p = 0.0230) Conclusions: The study suggests that a reduction in cocaine abuse and longer retention among MMT patients is mediated in part by variants in stress-related genes and is a step toward precision medicine.


Asunto(s)
Trastornos Relacionados con Cocaína , Trastornos Relacionados con Opioides , Analgésicos Opioides/uso terapéutico , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Humanos , Metadona/uso terapéutico , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Polimorfismo Genético
3.
Heredity (Edinb) ; 124(2): 325-335, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31712748

RESUMEN

The mu-opioid receptors (MOR, OPRM1) mediate the effects of beta-endorphin and modulate many biological functions including reward processing and addiction. The present study aimed to use bioinformatics to determine OPRM1 brain expression profiles in higher primates and to look for regulatory mechanisms. We used the same computational pipeline to analyze publicly available expression data from postmortem brain regions across humans, chimpanzees, and rhesus macaques. The most intriguing finding was high OPRM1 cerebellar expression in humans and chimpanzees and low expression in macaques. Together with previous reports of low cerebellar OPRM1 expression in mice, this suggests an evolutionary shift in the expression profiles. Bioinformatic analysis of the OPRM1 upstream region revealed a functional CTCF-binding region that evolved from tandem insertions of retrotransposons L1P1 and L1PA1 upstream (-60 kb) of OPRM1. The insertions arose in different time points after the split of small apes from great apes, and their combined sequence is unique. Furthermore, the derived G allele of SNP rs12191876, in the inserted region, is associated with an increased OPRM1 expression in the cerebellum of postmortem human brains (p = 4.7e-5). The derived G allele became the major allele (60-90%) in the populations represented in the 1000 Genomes Project and may be beneficial. This study provides a foundation for building new knowledge about evolutionary differences in OPRM1 brain expression. Further investigations are needed to elucidate the role of the inserted region and its SNPs in OPRM1 expression, and to assess the biological function and relevance of OPRM1 expression in the cerebellum.


Asunto(s)
Cerebelo/metabolismo , Evolución Molecular , Receptores Opioides mu/genética , Retroelementos , Alelos , Empalme Alternativo , Animales , Secuencia de Bases , Biología Computacional , Haplotipos , Hominidae/genética , Humanos , Macaca mulatta/genética , Mutagénesis Insercional , Pan troglodytes/genética , Polimorfismo de Nucleótido Simple , RNA-Seq
4.
Am J Drug Alcohol Abuse ; 46(6): 761-768, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32851876

RESUMEN

Background: Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/ kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse. Objectives: Determine whether gene variants in the opioid gene system are associated with better or worse treatment response. Methods: In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the National Drug Abuse Clinical Trials Network, DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N = 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to model each outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction. Results: There were no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions. Conclusions: The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.


Asunto(s)
Combinación Buprenorfina y Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Receptores Opioides/genética , Administración Sublingual , Adulto , Preparaciones de Acción Retardada/uso terapéutico , Femenino , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Naltrexona/uso terapéutico , Población Blanca/genética
5.
Ann Hum Genet ; 79(3): 188-98, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25875614

RESUMEN

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.


Asunto(s)
Trastornos Relacionados con Cocaína/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Predisposición Genética a la Enfermedad , Dependencia de Heroína/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Negro o Afroamericano/genética , Anciano , Estudios de Casos y Controles , Femenino , Genotipo , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Adulto Joven
6.
Ann Hum Genet ; 78(4): 290-8, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24766650

RESUMEN

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.


Asunto(s)
Negro o Afroamericano/genética , Predisposición Genética a la Enfermedad , Estrés Fisiológico/genética , Estrés Psicológico/genética , Trastornos Relacionados con Sustancias/etiología , Estudios de Casos y Controles , Biología Computacional , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple
7.
Nat Genet ; 37(9): 931-3, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16116424

RESUMEN

Seven Fanconi anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination. Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1.


Asunto(s)
Cromosomas Humanos Par 17 , Proteínas de Unión al ADN/genética , Anemia de Fanconi/genética , Mutación/genética , Polimorfismo de Nucleótido Simple , ARN Helicasas/genética , Ubiquitina/metabolismo , Western Blotting , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular , Proteínas de Unión al ADN/metabolismo , Proteína del Grupo de Complementación C de la Anemia de Fanconi , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi , Proteínas del Grupo de Complementación de la Anemia de Fanconi , Femenino , Humanos , Masculino , Repeticiones de Microsatélite , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linaje , ARN Helicasas/metabolismo
8.
Cytokine ; 64(2): 571-6, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24011637

RESUMEN

BACKGROUND: Chemokine receptors CCR2 and CCR5 play a key role in immune and inflammatory responses and have been associated with several diseases, including AIDS. In order to comprehend health disparities it is important to understand the nature of genetic variation in specific genes of interest in different populations. Current studies of the CCR2 and CCR5 receptor genes are primarily focused on the CCR5-Δ32, and CCR2-V64I SNPs. METHODS: Sanger sequencing was used to sequence the regions containing 16 SNPs in the adjacent CCR2 and CCR5 genes (including CCR5-Δ32, and CCR2-V64I) in 249 subjects of African, European and Hispanic ancestry. Linkage disequilibrium (LD) and haplotypes were determined using Haploview. RESULTS: The data revealed large differences in allele frequencies of several SNPs and LD patterns among the ethnic groups, including SNPs that were restricted to Africans or Europeans. Seven known CCR5 haplotypes and six novel CCR2 haplotypes were identified. A rare case of an HIV+ subject with the CCR5-Δ32/Δ32 was identified. CONCLUSIONS: These data demonstrate a LD between CCR2 and CCR5 at several loci and provide new information about CCR2 that contributes to our understanding of its population-specific genetic variability. The data indicate that in addition to CCR5-Δ32 and CCR2-V64I, other SNPs and haplotypes may be important genetic determinants of disease and should be investigated.


Asunto(s)
Variación Genética , Genética de Población , Desequilibrio de Ligamiento/genética , Receptores CCR2/genética , Receptores CCR5/genética , Adulto , Etnicidad/genética , Frecuencia de los Genes/genética , Genoma Humano/genética , Haplotipos/genética , Humanos , Masculino
9.
Hum Genomics ; 6: 2, 2012 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-23244743

RESUMEN

This study was designed to determine the ancestral composition of a multi-ethnic sample collected for studies of drug addictions in New York City and Las Vegas, and to examine the reliability of self-identified ethnicity and three-generation family history data. Ancestry biographical scores for seven clusters corresponding to world major geographical regions were obtained using STRUCTURE, based on genotypes of 168 ancestry informative markers (AIMs), for a sample of 1,291 African Americans (AA), European Americans (EA), and Hispanic Americans (HA) along with data from 1,051 HGDP-CEPH 'diversity panel' as a reference. Self-identified ethnicity and family history data, obtained in an interview, were accurate in identifying the individual major ancestry in the AA and the EA samples (approximately 99% and 95%, respectively) but were not useful for the HA sample and could not predict the extent of admixture in any group. The mean proportions of the combined clusters corresponding to European and Middle Eastern populations in the AA sample, revealed by AIMs analysis, were 0.13. The HA subjects, predominantly Puerto Ricans, showed a highly variable hybrid contribution pattern of clusters corresponding to Europe (0.27), Middle East (0.27), Africa (0.20), and Central Asia (0.14). The effect of admixture on allele frequencies is demonstrated for two single-nucleotide polymorphisms (118A > G, 17 C > T) of the mu opioid receptor gene (OPRM1). This study reiterates the importance of AIMs in defining ancestry, especially in admixed populations.


Asunto(s)
Salud de la Familia , Trastornos Relacionados con Sustancias/etnología , Trastornos Relacionados con Sustancias/genética , Encuestas y Cuestionarios , Negro o Afroamericano/genética , Frecuencia de los Genes , Genotipo , Hispánicos o Latinos/genética , Humanos , Nevada , New York , Polimorfismo de Nucleótido Simple , Receptores Opioides mu/genética , Estados Unidos , Población Blanca/genética
10.
Addict Biol ; 18(4): 709-16, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21790905

RESUMEN

Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose-response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP2D6. The CYP2B6*6 allele [single nucleotide polymorphisms (SNPs) 785A>G (rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism. To explore the effects of CYP2B6*6 allele on methadone dose requirement, it was genotyped in a well-characterized sample of 74 Israeli former heroin addicts in MMT. The sample is primarily of Middle Eastern/European ancestry, based on ancestry informative markers (AIMs). Only patients with no major co-medication that may affect methadone metabolism were included. The stabilizing daily methadone dose in this sample ranges between 13 and 260mg (mean 140±52mg). The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T (88, 96mg, respectively) were significantly lower than those of the heterozygotes (133, 129mg, respectively) and the non-carriers (150, 151mg, respectively) (nominal P=0.012, 0.048, respectively). The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), which was previously shown to be associated with high methadone dose requirement in this population (P=0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these, 24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other populations.


Asunto(s)
Analgésicos Opioides/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Etnicidad/genética , Metadona/administración & dosificación , Oxidorreductasas N-Desmetilantes/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacocinética , Análisis de Varianza , Citocromo P-450 CYP2B6 , Relación Dosis-Respuesta a Droga , Etnicidad/etnología , Femenino , Frecuencia de los Genes , Heterocigoto , Homocigoto , Humanos , Israel/etnología , Desequilibrio de Ligamiento , Masculino , Metadona/metabolismo , Metadona/farmacocinética , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/genética , Farmacogenética , Medicina de Precisión , Análisis de Secuencia de ADN/métodos , Adulto Joven
11.
J Infect Dis ; 205(11): 1745-56, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22457278

RESUMEN

BACKGROUND: Mu opioid receptor (OPRM1) ligands may alter expression of chemokines and chemokine receptors involved in penetration of human immunodeficiency virus (HIV) type 1 into the cell. We suggest that OPRM1 variants may affect the pathophysiology of HIV infection. METHODS: DNA samples from 1031 eligible African Americans, Hispanics, and whites from the Women's Interagency HIV Study (WIHS) who were alive as of April 2006 were analyzed. We performed regression analysis of association of 18 OPRM1 variants with a change of viral load and CD4 cell count during 2 periods: between admission to WIHS and the start of highly active antiretroviral therapy (HAART) (interval X) and between the start of HAART and the most recent WIHS visit (interval Y), and examined the association of these variants with HIV status. RESULTS: Regardless of genotype, a significant decrease in viral load during interval X was found for each ethnicity. Whites with allele G of the functional polymorphism 118A > G (reference sequence rs1799971) showed a smaller decrease in viral load; those bearing minor alleles IVS1 + 1050A, IVS1 + 14123A, and IVS2 + 31A showed a larger decrease in viral load over interval X (0.01 < P < .05). Hispanics with the same alleles showed a greater increase in CD4 cell count over interval Y (0.01 < P < .05). We found an association between OPRM1 variants and HIV status in African Americans and whites. CONCLUSIONS: OPRM1 polymorphisms may alter the severity of HIV infection before and after HAART.


Asunto(s)
Infecciones por VIH/genética , VIH-1/aislamiento & purificación , Polimorfismo Genético , Receptores Opioides mu/genética , Carga Viral , Negro o Afroamericano , Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Hispánicos o Latinos , Humanos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Población Blanca
12.
Drug Alcohol Depend ; 250: 110903, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37531661

RESUMEN

BACKGROUND: Variants in the delta opioid receptor gene, OPRD1, were associated with opioid use disorder and response to treatment. The study goal was to assess whether OPRD1 variants predict survival and retention in methadone maintenance treatment (MMT). METHODS: Retention and survival time since admission (June 1993 - June 2022) until leaving treatment (for retention), or at the end of follow-up (Dec 2022) (for retention and survival) were analyzed in 488 patients. Vital data was taken from a national registry. Predictors were estimated using Kaplan-Meier and Cox regression models. RESULTS: Longer retention and survival were found for carriers of the T allele of SNP rs204076. This SNP is associated with OPRD1 expression in cortex (GTEx). Carriers of the T allele (n = 251) survived longer compared to non-carriers (24.7 vs. 20.2 years, p = 0.005) and had longer retention (11.2 vs. 8.8 years, p = 0.04). Multivariate analysis identified the T allele as an independent predictor of longer survival time (p = 0.003) and retention (p = 0.009). Additional predictors for survival were no benzodiazepine use after one year in MMT, no hepatitis C, <20 years of opioid usage, and admission at age < 30. Additional predictors for longer retention were no use of other drugs except opioids on admission, and no drugs at one year, as well as methadone dose ≥ 100mg/d at one year and axis I & II DSM-5 psychiatric diagnosis. CONCLUSIONS: The OPRD1 SNP rs204076 and non-genetic predictors contribute to survival time and retention in MMT patients.


Asunto(s)
Trastornos Relacionados con Opioides , Receptores Opioides delta , Humanos , Receptores Opioides delta/genética , Receptores Opioides delta/uso terapéutico , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Opioides/psicología , Analgésicos Opioides/uso terapéutico , Benzodiazepinas/uso terapéutico , Tratamiento de Sustitución de Opiáceos
13.
Hum Genet ; 131(6): 823-42, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22547174

RESUMEN

Addiction to drugs is a chronic, relapsing brain disease that has major medical, social, and economic complications. It has been established that genetic factors contribute to the vulnerability to develop drug addiction and to the effectiveness of its treatment. Identification of these factors may increase our understanding of the disorders, help in the development of new treatments and advance personalized medicine. In this review, we will describe the genetics of the major genes of the opioid system (opioid receptors and their endogenous ligands) in connection to addiction to opioids, cocaine, alcohol and methamphetamines. Particular emphasis is given to association and functional studies of specific variants. We will provide information on the sample populations and the size of each study, as well as a list of the variants implicated in association with addiction-related phenotypes, and with the effectiveness of pharmacotherapy for addiction.


Asunto(s)
Variación Genética , Antagonistas de Narcóticos/farmacología , Fenotipo , Receptores Opioides/genética , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos
14.
Sci Rep ; 12(1): 16873, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-36207451

RESUMEN

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.


Asunto(s)
Estudio de Asociación del Genoma Completo , Trastornos Relacionados con Opioides , Furina/genética , Predisposición Genética a la Enfermedad , Humanos , Trastornos Relacionados con Opioides/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Receptores Opioides mu/genética
15.
Pharmacogenet Genomics ; 21(4): 185-96, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20808262

RESUMEN

OBJECTIVE: Dynorphins, the endogenous ligands for the κ opioid receptor, are implicated in neuropsychiatric disorders through modulation of basal and stimuli-induced dopaminergic, glutamatergic, and serotonergic tones. Expression of the prodynorphin gene (PDYN) is critical for rewarding properties of drugs of abuse and stress-induced responses. Epigenetic factors, such as DNA methylation, play an important role in modulation of gene expression. METHODS: We analyzed DNA methylation patterns of three CpG-rich regions of PDYN, a CpG island, and cluster A in the proximal promoter, and cluster B in coding exon 4, by bisulfite sequencing of DNA from the caudate and anterior cingulate cortex from post-mortem brain of 35 individuals (22 HIV seropositive), and in peripheral blood mononuclear cells from 21 of these individuals. RESULTS: We found remarkably similar patterns of methylation across CpG sites in these tissues. However, there were tissue-specific differences in methylation levels (P=0.000001) of the CpG island: higher levels in peripheral blood mononuclear cells (82%) than in the brain tissues, the caudate (62%), and the anterior cingulate cortex (44%). But there was higher PDYN expression in the caudate than in the anterior cingulate cortex. In contrast, cluster A near the transcription start site is hypomethylated. CONCLUSION: This DNA methylation profile of the PDYN gene is typical for primary responsive genes with regulatory elements for both basal and tissue-specific transcription. Our findings provide a rationale for further studies of the role of other epigenetic factors in the regulation of PDYN expression in individuals with psychiatric and neurological disorders.


Asunto(s)
Encéfalo/metabolismo , Metilación de ADN , Encefalinas/genética , Precursores de Proteínas/genética , Islas de CpG , Epigenómica , Humanos , Leucocitos Mononucleares/metabolismo , ARN Mensajero/metabolismo
16.
J Hum Genet ; 56(2): 147-55, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21160491

RESUMEN

The opioid system is involved in the action of opiate drugs, opioid addiction, pain experience and analgesia. Individual differences in opioid effect may be attributed in part to genetic variations. Long-range cis regulatory elements and intronic variants are potential sources of functional diversity. Recently, we have detected association of two intronic OPRM1 variants with heroin addiction in European Americans. In this study, we analyzed the genetic variations in the OPRM1 100 kb 5'-flanking region and intron 1 in the HapMap Caucasian population. Four major linkage disequilibrium blocks were identified, consisting of 28, 22, 15 and 42 single-nucleotide polymorphisms (SNPs), respectively. The locations of these blocks are (-100 to -90), (-90 to -67), (-20 to -1) and (+1 to +44) kb, respectively. The two intronic variants, indicated in our recent study, are part of a distinct haplogroup that includes SNPs from intron 1, and the proximal 5' region. The 118G (rs1799971) allele is part of a different haplogroup that includes several variants in the distal 5' region that may have a regulatory potential. These findings were corroborated by genotyping eight SNPs in a sample of European Americans and suggest an extended OPRM1 locus with potential new regulatory regions.


Asunto(s)
Variación Genética , Genoma , Haplotipos , Receptores Opioides mu/genética , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Genotipo , Humanos , Intrones , Desequilibrio de Ligamiento , Estudios Multicéntricos como Asunto , Polimorfismo de Nucleótido Simple , Valores de Referencia , Secuencias Reguladoras de Ácidos Nucleicos , Población Blanca/genética
17.
Transl Psychiatry ; 11(1): 316, 2021 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-34031368

RESUMEN

Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype ('Hap 3') that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for 'Hap 3' were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.


Asunto(s)
Actinas , Trastornos Relacionados con Opioides , Estudios de Seguimiento , Haplotipos , Humanos , Trastornos Relacionados con Opioides/genética , Monoéster Fosfórico Hidrolasas , Polimorfismo de Nucleótido Simple , Receptores Opioides delta/genética
18.
Hum Mol Genet ; 17(14): 2219-27, 2008 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-18424454

RESUMEN

Methadone is a mu-opioid receptor agonist used for treating opiate dependence. The range of effective methadone doses is broad. Part of the large inter-individual variability in efficacy may be accounted for by genetic factors. Methadone is a substrate of the transporter P-glycoprotein (P-gp) 170 that is encoded by the ABCB1 (MDR1) gene. Thus, P-gp variants may play a role in methadone absorption and distribution. We assessed the association between ABCB1 polymorphisms and methadone dose requirements in 98 methadone-maintained patients. The stabilizing methadone doses were normally distributed with a mean and median dose of 160 mg/day (range 30-280 mg/day). Statistical analysis showed significant difference in genotype frequencies between the 'higher' (>150 mg/day) and 'lower' (< or =150 mg/day) methadone dose groups for single nucleotide polymorphism (SNP) 1236C>T (rs1128503) (experiment-wise P = 0.0325). Furthermore, individuals bearing the 3-locus genotype pattern TT-TT-TT (rs1045642, rs2032582 and rs1128503) have an approximately 5-fold chance of requiring the 'higher' methadone dose, while individuals heterozygous for these three SNPs have an approximately 3-fold chance of stabilizing at the 'lower' methadone dose (point-wise P-value = 0.026). These data suggest that specific ABCB1 variants may have clinical relevance by influencing the methadone dose required to prevent withdrawal symptoms and relapse in this population.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Dependencia de Heroína/tratamiento farmacológico , Metadona/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Variación Genética , Humanos , Israel/etnología , Judíos/genética , Desequilibrio de Ligamiento , Masculino , Metadona/uso terapéutico , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
19.
Curr Opin Pharmacol ; 9(1): 74-80, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19155191

RESUMEN

This review primarily focuses on our recent findings in bidirectional translational research on opiate and cocaine addictions. First, we present neurobiological and molecular studies on endogenous opioid systems (e.g. proopiomelanocortin, mu opioid receptor, dynorphin, and kappa opioid receptor), brain stress-responsive systems (e.g. orexin, arginine vasopressin, V1b receptor, and corticotropin-releasing factor), hypothalamic-pituitary-adrenal axis, and neurotransmitters (especially dopamine), in response to both chronic cocaine or opiate exposure and to drug withdrawal, using several newly developed animal models and molecular approaches. The second aspect is human molecular genetic association investigations including hypothesis-driven studies and genome-wide array studies, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy.


Asunto(s)
Conducta Adictiva/metabolismo , Cocaína/farmacología , Heroína/farmacología , Narcóticos/farmacología , Trastornos Relacionados con Opioides/metabolismo , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Conducta Adictiva/genética , Conducta Adictiva/fisiopatología , Conducta Adictiva/psicología , Estudio de Asociación del Genoma Completo , Humanos , Ligandos , Metadona/farmacología , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Opioides/fisiopatología , Farmacogenética , Receptores Opioides/genética , Receptores Opioides/metabolismo
20.
Pharmacogenomics ; 21(13): 903-917, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32757697

RESUMEN

Aim: Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD). Patients & methods: One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls. Results: Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect: NPY1R/GAL rs4691910/rs1893679, NPY1R/GAL rs4691910/rs3136541 and GALR1/GAL rs9807208/rs3136541. Conclusion: This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Trastornos Relacionados con Opioides/genética , Polimorfismo de Nucleótido Simple/genética , Receptor de Galanina Tipo 1/genética , Receptores de Neuropéptido Y/genética , Adulto , Estudios de Casos y Controles , Femenino , Genotipo , Haplotipos/genética , Heroína/uso terapéutico , Dependencia de Heroína/genética , Humanos , Masculino , Metadona/uso terapéutico , Tratamiento de Sustitución de Opiáceos/métodos
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