RESUMEN
Genome-wide studies provide increasing evidence of association of genetic variants with different behaviors. However, there is a growing need for replication and subsequent characterization of specific findings. In this sense, the CHRNA5 gene has been associated with nicotine (with genome-wide significance), alcohol and cocaine addictions. So far, this gene has not been evaluated in smoked (crack) cocaine. We aimed to analyze the influence of CHRNA5 variants in crack addiction susceptibility and severity. The sample includes 300 crack-addicted patients and 769 non-addicted individuals. The CHRNA5 SNPs evaluated were rs588765, rs16969968, and rs514743. Homozygosity for rs16969968 and rs588765 major alleles was nominally associated with a risk to crack addiction (GG, P = 0.032; CC, P = 0.036, respectively). Haplotype analyses reveal significant associations (rs588765|rs16969968|rs514743 pglobal-corrected = 7.66 × 10-5) and suggest a substantial role for rs16969968. These findings corroborate previous reports in cocaine addiction-in line with the expected effects of cocaine in the cholinergic system-and in the opposite direction of significant GWAS findings for nicotine addiction susceptibility. These results are strengthened by the first report of an association of rs588765 with crack addiction and by the haplotype findings. In summary, our study highlights the relevance of the α5 subunit on crack cocaine addiction, replicating previous results relating CHRNA5 with the genetics and pathophysiology of addiction of different drugs.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Cocaína Crack/efectos adversos , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Receptores Nicotínicos/genética , Adulto , Alelos , Estudios de Casos y Controles , Trastornos Relacionados con Cocaína/epidemiología , Simulación por Computador , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos/genética , Humanos , Masculino , Riesgo , Relación Estructura-Actividad , Adulto JovenRESUMEN
BACKGROUND: The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status. METHODS: The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (Pcorr=0.034) and rs878886 in men (Pcorr=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups. CONCLUSIONS: Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.
Asunto(s)
Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Receptores de Hormona Liberadora de Corticotropina/genética , Fumar/efectos adversos , Adulto , Brasil , Estudios Transversales , Trastorno Depresivo Mayor/etiología , Femenino , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Factores Sexuales , Población Blanca , Adulto JovenRESUMEN
Crack cocaine addicted inpatients that present more severe withdrawal symptoms also exhibit higher rates of depressive symptoms. There is strong evidence that the identification of genetic variants in depression is potentialized when reducing phenotypic heterogeneity by studying selected groups. Since depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis, this study evaluated the effects of SNPs in stress-related genes on depressive symptoms of crack cocaine addicts at early abstinence and over the detoxification treatment (4th, 11th and 18th day post admission). Also, the role of these SNPs on the re-hospitalization rates after 2.5 years of follow-up was studied. One hundred eight-two women were enrolled and eight SNPs in four genes (NR3C2, NR3C1, FKBP5 and CRHR1) were genotyped. A significant main effect of NR3C1-rs41423247 was found, where the C minor allele increased depressive symptoms at early abstinence. This effect remained significant after 10,000 permutations to account for multiple SNPs tested (P=0.0077). There was no effect of rs41423247 on the course of detoxification treatment, but a slight effect of rs41423247 at late abstinence was detected (P=0.0463). This analysis suggests that the presence of at least one C allele is worse at early abstinence, while only CC genotype appears to increase depressive symptoms at late abstinence. Also, a slight effect of rs41423247 C minor allele increasing the number of re-hospitalizations after 2.5 years was found (P=0.0413). These findings are in agreement with previous studies reporting an influence of rs41423247 on sensitivity to glucocorticoids and further elucidate its resulting effects on depressive-related traits.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/psicología , Cocaína Crack , Depresión/genética , Polimorfismo de Nucleótido Simple , Receptores de Glucocorticoides/genética , Adulto , Trastornos Relacionados con Cocaína/terapia , Depresión/terapia , Femenino , Estudios de Seguimiento , Técnicas de Genotipaje , Hospitalización , Humanos , Estudios Longitudinales , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Mineralocorticoides/genética , Análisis de Regresión , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/psicología , Proteínas de Unión a Tacrolimus/genética , Adulto JovenRESUMEN
The aim of this study was to analyze hypotheses-driven gene-environment and gene-gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in mineralocorticoid and glucocorticoid receptor genes (NR3C2 and NR3C1, respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values ≤ 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes.