RESUMEN
Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity. METHODS: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately. RESULTS: Cocaine dependence (poccurrence= 6.18 × 10-5, pseverity= 9.25 × 10-8), number of cocaine dependence DSM IV-Tr criteria (poccurrence= 1.22 × 10-7, pseverity= 5.09 × 10-6), and frequency of intake during the worst period of misuse (poccurrence= 8.51 × 10-04, pseverity= 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs. CONCLUSION: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.
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Trastornos Relacionados con Cocaína , Cocaína , Trastornos Relacionados con Cocaína/complicaciones , Trastornos Relacionados con Cocaína/epidemiología , Trastornos Relacionados con Cocaína/genética , Alucinaciones/inducido químicamente , Alucinaciones/epidemiología , Alucinaciones/genética , Humanos , Fenotipo , Factores de RiesgoRESUMEN
Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.
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Factor Neurotrófico Derivado del Encéfalo , Trastornos Relacionados con Sustancias , Ideación Suicida , Teorema de Bayes , Factor Neurotrófico Derivado del Encéfalo/genética , Análisis por Conglomerados , Humanos , Fenotipo , Factores de Riesgo , Trastornos Relacionados con Sustancias/genéticaRESUMEN
Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (N = 40), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, Lrp1b, was differentially expressed in both regions. In patients, LRP1B was significantly associated with both CIS and CIH. CIH was also associated with VPS13A, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The LRP1B minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected p = 0.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta = -0.965 and -2.35 for heterozygotes and homozygotes, respectively, p < 0.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that LRP1B and VPS13A are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.
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Trastornos Relacionados con Cocaína , Cocaína , Receptores de LDL , Estriado Ventral , Proteínas de Transporte Vesicular , Animales , Trastornos Relacionados con Cocaína/genética , Cuerpo Estriado , Humanos , Polimorfismo Genético , Ratas , TranscriptomaRESUMEN
Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (rPearson = 0.26; P = 10-3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10-4 ; pcorrected = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (pempirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients' genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.
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Síndrome de QT Prolongado/inducido químicamente , Metadona/efectos adversos , Tratamiento de Sustitución de Opiáceos/efectos adversos , Canales de Potasio con Entrada de Voltaje/genética , Adulto , Relación Dosis-Respuesta a Droga , Electrocardiografía , Femenino , Predisposición Genética a la Enfermedad , Dependencia de Heroína/tratamiento farmacológico , Humanos , Síndrome de QT Prolongado/genética , Masculino , Metadona/administración & dosificación , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos/métodos , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
ABCG4 is an ATP-binding cassette transmembrane protein which has been shown, in vitro, to participate in the cellular efflux of desmosterol and amyloid-ß peptide (Aß). ABCG4 is highly expressed in the brain, but its localization and function at the blood-brain barrier (BBB) level remain unknown. We demonstrate by qRT-PCR and confocal imaging that mouse Abcg4 is expressed in the brain capillary endothelial cells. Modelling studies of the Abcg4 dimer suggested that desmosterol showed thermodynamically favorable binding at the putative sterol-binding site, and this was greater than for cholesterol. Additionally, unbiased docking also showed Aß binding at this site. Using a novel Abcg4-deficient mouse model, we show that Abcg4 was able to export Aß and desmosterol at the BBB level and these processes could be inhibited by probucol and L-thyroxine. Our assay also showed that desmosterol antagonized the export of Aß, presumably as both bind at the sterol-binding site on Abcg4. We show for the first time that Abcg4 may function in vivo to export Aß at the BBB, in a process that can be antagonized by its putative natural ligand, desmosterol (and possibly cholesterol).
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Transportador de Casetes de Unión a ATP, Subfamilia G/genética , Transportador de Casetes de Unión a ATP, Subfamilia G/metabolismo , Péptidos beta-Amiloides/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Expresión Génica , Transportador de Casetes de Unión a ATP, Subfamilia G/química , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Péptidos beta-Amiloides/química , Animales , Biomarcadores , Permeabilidad Capilar , Permeabilidad de la Membrana Celular , Desmosterol/metabolismo , Técnica del Anticuerpo Fluorescente , Marcación de Gen , Sitios Genéticos , Ratones , Ratones Noqueados , Modelos Moleculares , Unión Proteica , Conformación Proteica , Multimerización de Proteína , Relación Estructura-ActividadRESUMEN
BACKGROUND AND OBJECTIVES: The burden of opiate dependence not only relies on somatic complications such as infectious diseases or acute intoxication but also on frequent psychiatric events such as major depressive disorder (MDD) and suicidal behavior (SB). Given the preclinical and clinical evidence regarding the associations between cannabinoid systems and both opiate dependence and psychiatric disorders, we chose to address whether one single nucleotide polymorphism (SNP) of the cannabinoid receptor type 1 gene (CNR1) named rs2023239 would be associated with lifetime MDD and SB in a population of opiate-dependent outpatients remitted under stable methadone treatment. METHODS: Sociodemographic and clinical data were included as independent factors in two logistic regression models aimed at predicting SB and MDD, respectively, performed with 85 Caucasian individuals. RESULTS: The minor C allele of rs2023239 showed an independent protective effect against lifetime MDD after adjustment for potential confounders. It was not associated with variables related to suicidal behavior. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Despite limitations due to the modest sample size, our results are consistent with previous research on the endocannabinoid system and suggest new leads for detecting subjects at risk of MDD, which remains insufficiently diagnosed and treated in patients suffering from severe addictive disorders.
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Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/genética , Metadona/uso terapéutico , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/tratamiento farmacológico , Polimorfismo de Nucleótido Simple/genética , Receptor Cannabinoide CB1/genética , Adulto , Alelos , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Relacionados con Opioides/genética , Trastornos Relacionados con Opioides/psicología , Pacientes Ambulatorios/psicología , Factores Protectores , Ideación Suicida , Adulto JovenRESUMEN
BACKGROUND: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. METHODS: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. RESULTS: The mean QTc interval was 415±34ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4ms longer QTc (95% CI [4.6-26.2]; p=0.001). CONCLUSION: KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.
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Canales de Potasio Éter-A-Go-Go/genética , Sistema de Conducción Cardíaco/efectos de los fármacos , Dependencia de Heroína/tratamiento farmacológico , Metadona/administración & dosificación , Narcóticos/administración & dosificación , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Canal de Potasio ERG1 , Femenino , Interacción Gen-Ambiente , Genotipo , Corazón/efectos de los fármacos , Dependencia de Heroína/genética , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/genética , Masculino , Metadona/efectos adversos , Metadona/uso terapéutico , Persona de Mediana Edad , Narcóticos/efectos adversos , Narcóticos/uso terapéutico , Tratamiento de Sustitución de Opiáceos , Adulto JovenRESUMEN
Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as "FHL5"). Lymphoblasts isolated from these patients had strongly decreased STXBP2 protein expression, and NK cells exhibited impaired cytotoxic granule exocytosis, a defect that could be overcome by ectopic expression of wild-type STXBP2. Furthermore, we provide evidence that syntaxin-11 is the main partner of STXBP2 in lymphocytes, as its expression required the presence of STXBP2. Our work shows that STXBP2 deficiency causes FHL5. These data indicate that STXBP2 is required at a late step of the secretory pathway for the release of cytotoxic granules by binding syntaxin 11, another component of the intracellular membrane fusion machinery.