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BACKGROUND: There is growing evidence that the anticonvulsant topiramate is efficacious in reducing alcohol consumption. Further, an intronic single nucleotide polymorphism (rs2832407, C A) in the GRIK1 gene, which encodes the GluK1 subunit of the excitatory kainate receptor, predicted topiramate's effectiveness in reducing heavy drinking in a clinical trial. The molecular correlates of GRIK1 genotype that may relate to topiramate's ability to reduce drinking remain unknown. METHODS: We differentiated induced pluripotent stem cells (iPSCs) characterized by GRIK1 rs2832407 genotype from 8 A/A and 8 C/C donors into forebrain-lineage neural cultures. Our differentiation protocol yielded mixed neural cultures enriched for glutamatergic neurons. Basal mRNA expression of the GRIK1 locus was examined via quantitative polymerase chain reaction (qPCR). The effects of acute topiramate exposure on excitatory spontaneous synaptic activity were examined via whole-cell patch-clamp electrophysiology. Results were compared and contrasted between iPSC donor genotypes. RESULTS: Although characterization of the GRIK1 locus revealed no effect of rs2832407 genotype on GRIK1 isoform mRNA expression, a significant difference was observed on GRIK1 antisense-2 expression, which was greater in C/C neural cultures. Differential effects of acute exposure to 5 µM topiramate were observed on spontaneous synaptic activity in A/A versus C/C neurons, with a smaller reduction in excitatory event frequency observed in C/C donor neurons. CONCLUSIONS: This work highlights the use of iPSC technologies to study pharmacogenetic treatment effects in psychiatric disorders and furthers our understanding of the molecular effects of topiramate exposure in human neural cells.
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Anticonvulsivantes/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Neurônios/efeitos dos fármacos , RNA Antissenso/metabolismo , RNA Mensageiro/metabolismo , Receptores de Ácido Caínico/genética , Topiramato/farmacologia , Potenciais Pós-Sinápticos Excitadores/genética , Genótipo , Humanos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Variantes Farmacogenômicos , Células-Tronco Pluripotentes , Polimorfismo de Nucleotídeo Único , Receptores de Ácido Caínico/metabolismoRESUMO
INTRODUCTION: Characterizing flavors are widely available in e-cigarettes and motivate initiation and continued use. Flavors may enhance appeal and facilitate development of addiction to tobacco products through modulation of tobacco products' reinforcing or aversive actions. Palatable flavors (eg, fruit) may increase appeal through primary reinforcing properties. Menthol's cooling and anesthetic effects may increase appeal by counteracting nicotine's aversive effects. Genetics provide a method for modeling individual differences in sensitivity to nicotine's effects. A common polymorphism, rs16969968, encoded in the α5 nicotinic acetylcholine receptor subunit gene (CHRNA5), is a well-recognized marker for smoking risk and reduces sensitivity to nicotine aversiveness. METHODS: This pilot study tested how flavors impacted e-cigarette appeal and self-administration. In a single testing day, cigarette smokers (N = 32; 94% menthol-smokers) self-administered e-cigarettes containing e-liquids differing in nicotine level (0 mg/mL, 24 mg/mL) and flavor (unflavored, menthol, fruit-flavored) within directed and ad libitum e-cigarette paradigms. Subjective drug effects, number of puffs, rs16969968 genotype, plasma nicotine, and menthol glucuronide levels were collected. RESULTS: Menthol partially ameliorated nicotine aversiveness; fruit did not. In nicotine's absence, fruit flavor increased self-reported preference and ad libitum use relative to menthol-containing or unflavored e-liquids. Individuals with high-smoking-risk rs16969968 genotype (N = 7) reported greater craving alleviation following directed administration of nicotine-containing e-liquids, showed a trend rating nicotine-containing e-liquids as less harsh, and self-administered more nicotine during ad libitum compared to individuals with low-smoking-risk genotype (N = 23). CONCLUSIONS: While menthol countered aversiveness of nicotine-containing e-liquids, fruit flavor increased appeal of nicotine-free e-liquids. These preliminary findings suggest menthol and fruit flavor increase e-cigarettes' appeal through distinct mechanisms. IMPLICATIONS: This study provides a detailed characterization of the effects of flavors (unflavored, menthol, fruit), nicotine (0 mg/mL, 24 mg/mL) and their interactions on the subjective drug effects and ad libitum self-administration of e-cigarettes. Genetics were used to assess these effects in higher-smoking-risk (diminished sensitivity to nicotine aversiveness) and lower-risk groups. Findings could inform impact of regulation of flavors or nicotine in e-cigarettes, and their impacts on vulnerable sub-populations.
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Aromatizantes/farmacologia , Nicotina/farmacologia , Substâncias Protetoras/farmacologia , Reforço Psicológico , Fumantes/psicologia , Fumar/tratamento farmacológico , Adolescente , Adulto , Connecticut/epidemiologia , Fissura/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fumar/epidemiologia , Fumar/psicologia , Paladar/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.
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Convulsões por Abstinência de Álcool/genética , Receptores de Superfície Celular/genética , Adulto , População Negra , Linhagem Celular , Biologia Computacional , Dexametasona/farmacologia , Feminino , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População BrancaRESUMO
Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h2g = 0.12, P = 2.17 × 10-4 in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P = 1.55 × 10-8 ; beta = 0.073) and AFR (rs78924501, Chr 1: BP 88406905, P = 3.58 × 10-8 ; beta = 0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (rg = -0.52, se = 0.22, P = 0.02) but not with neuroticism (rg = 0.05, se = 0.22, P = 0.81) or with an anxiety disorder factor score (rg = 0.02, se = 0.32, P = 0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. © 2017 Wiley Periodicals, Inc.
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Ansiedade/genética , Fobia Social/genética , Adulto , Ansiedade/psicologia , Transtornos de Ansiedade/genética , Extroversão Psicológica , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Militares/psicologia , Neuroticismo , Personalidade/genética , Fenótipo , Fobia Social/psicologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: PTSD and cigarette smoking frequently co-occur for reasons that are not well understood. The current behavioral and pharmacological treatments and emerging new treatment targets for smoking cessation are discussed. METHODS: Here we describe recent research on PTSD and smoking with an emphasis on 1) the clinical characteristics of smokers with PTSD, 2) smoking treatment trials that specifically targeted smokers with PTSD, 3) recent research on stress-response and affect regulation pathways that might link the two disorders and 4) potential ways to leverage new findings on stress response systems and affect regulation mechanisms to improve treatment outcomes for smokers with PTSD. RESULTS: Smokers with PTSD have higher rates of smoking compared to the general population and have greater difficulty quitting compared to smokers without PTSD. There have been several studies of adjunctive and integrated smoking cessation interventions for smokers with PTSD, but fewer tailored interventions that intensively target stress-response pathways or affect regulation related to both tobacco use and PTSD. Stress-response pathways and affect regulation appear to be important mechanisms involved in the development and maintenance of smoking in individuals with PTSD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Additional research that focuses on smokers with PTSD is warranted given that successful tobacco treatment response is low and the negative health effects of each disorder can be greatly amplified.
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Abandono do Hábito de Fumar/psicologia , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/terapia , Tabagismo/complicações , Tabagismo/terapia , Terapia Combinada , Diagnóstico Duplo (Psiquiatria) , Humanos , Resultado do TratamentoRESUMO
Functional variants that contribute to genomewide association study (GWAS) signals are difficult to identify. MicroRNAs could contribute to some of these gene-trait relationships. We compiled a set of GWAS trait gene SNPs that were predicted to affect microRNA regulation of mRNA. Trait associations were tested in a sample of 6725 European-American (EA) and African-American (AA) subjects that were interviewed using the polydiagnostic SSADDA to diagnose major psychiatric disorders. A predicted miR-330-3p target site SNP (rs41305272) in mitogen-activated protein kinase kinase 5 (MAP2K5) mRNA was in LD (d' = 1.0, r(2) = 0.02) with a reported GWAS-identified variant for restless legs syndrome (RLS), a disorder frequently comorbid with anxiety and depression, possibly because of a shared pathophysiology. We examined the SNP's association with mood and anxiety-related disorders. Rs41305272 was associated with agoraphobia (Ag) in EAs (odds ratio [OR] = 1.95, P = 0.007; 195 cases) and AAs (OR = 3.2, P = 0.03; 148 cases) and major depressive disorder (MDD) in AAs (OR = 2.64, P = 0.01; 427 cases), but not EAs (465 cases). Rs41305272*T carrier frequency was correlated with the number of anxiety and depressive disorders diagnosed per subject. RLS was not evaluated in our subjects. Predicted miR-330-3p target genes were enriched in pathways relevant to psychiatric disorders. These findings suggest that microRNA target site information may be useful in the analysis of GWAS signals for complex traits. MiR-330-3p and MAP2K5 are potentially important contributors to mood and anxiety-related traits. With support from additional studies, these findings could add to the large number of risk genes identified through association to medical disorders that have primary psychiatric effects.
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Transtornos de Ansiedade/genética , Transtorno Depressivo/genética , MAP Quinase Quinase 5/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Transtornos de Ansiedade/complicações , Transtorno Depressivo/complicações , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , RiscoRESUMO
Recent deep-sequencing efforts have identified many novel non-conserved small RNAs that are expressed at low levels in certain mammalian cells. Whether these small RNAs are important for mammalian physiology is debatable, therefore we explored the function of one such RNA, human miR-1271. This small RNA is similar in sequence to miR-96, a highly conserved microRNA that when mutated causes hearing loss in humans and mice. Although the miR-1271 and miR-96 sequences differ slightly, our in vitro assays indicate that they have an identical regulatory activity. We have identified brain-expressed mRNAs from genes including, GPHN, RGS2, HOMER1 and KCC2, which share the same miR-96 and miR-1271 regulatory elements. Interestingly, human miR-1271 is expressed abundantly in brain tissue, where miR-96 is not highly expressed. The rodent miR-1271 precursor contains several sequence differences in the precursor stem, which appear to reduce the efficiency of microRNA processing. Our data indicate that although miR-1271 and miR-96 function identically in vitro, they function to some extent uniquely in vivo. Given the expression patterns and nature of the target genes, miR-1271 may have a significant, although non-conserved, role in regulating aspects of neural development or function in humans.
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Encéfalo/metabolismo , MicroRNAs/metabolismo , Animais , Regulação da Expressão Gênica , Células HEK293 , Humanos , MicroRNAs/química , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Ratos , Transdução de SinaisRESUMO
Small RNAs modulate gene expression by forming a ribonucleoprotein complex with Argonaute proteins and directing them to specific complementary sites in target nucleic acids. However, the interactions required for the recruitment of the target nucleic acid to the ribonucleoprotein complex are poorly understood. In the present manuscript we have investigated this question by using let-7a, Argonaute2 and a fully complementary mRNA target. Importantly, we have found that recombinant Argonaute2 is sufficient to direct let-7a guided cleavage of mRNA. Thus this model system has allowed us to investigate the mechanistic basis of silencing in vitro and in vivo. Current models suggest that Argonaute proteins bind to both the 5' and 3' termini of the guide RNA. We have found that the termini of the let-7a microRNA are indeed critical, since circular let-7a does not support mRNA cleavage. However, the 5' end is the key determinant, since its deletion abrogates activity. Surprisingly, we have found that alteration of the 5' terminal uracil compromises mRNA cleavage. Importantly, we have found that substitution of this base has little effect upon the formation of the binary let-7a-Argonaute2 complex, but inhibits the formation of the ternary let-7a-Argonaute2-mRNA complex. Thus we conclude that the interaction of the 5' uracil base with Argonaute2 plays a critical and novel role in the recruitment of mRNA.
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Regiões 5' não Traduzidas/genética , Fator de Iniciação 2 em Eucariotos/química , Fator de Iniciação 2 em Eucariotos/genética , MicroRNAs/química , RNA Mensageiro/genética , Uracila/química , Proteínas Argonautas , Sequência Conservada/genética , Células HeLa , Humanos , MicroRNAs/metabolismo , Estrutura Terciária de Proteína/genética , RNA Mensageiro/química , Ribonucleoproteínas/biossíntese , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Uracila/fisiologia , Pequeno RNA não TraduzidoRESUMO
We examined associations between haplotypes of the serotonin 1B receptor gene and individual differences in anger and hostility. Data were analyzed from a study of 361 university students (47% male). Participants were genotyped at five polymorphisms in the HTR1B gene (rs11568817, rs130058, rs6296, rs6297, rs13212041), including promoter and 3'UTR polymorphisms with opposite functional effects on gene expression. Participants reported their emotional states across 30 consecutive days for up to 4 years. Haplotype pairs were constructed statistically and assigned to a level of HTR1B expression based on the presence of the functional polymorphisms. Six haplotypes accounted for >97% of chromosomes. Three low expression haplotypes contained the 3'UTR variant (rs13212041 A-allele) that enables a microRNA-mediated reduction in expression. One intermediate expression haplotype contained the 3'UTR A-allele paired with the high-activity promoter. Two high expression haplotypes contained the 3'UTR variant (rs13212041 G-allele) that attenuates microRNA-mediated reduction in expression. Men with low expression haplotypes reported greater anger and hostility than men with one or two high expression haplotypes. Diplotype classification accounted for 8.4% of the variance in men's anger and hostility, primarily due to the 3'UTR polymorphism (rs13212041), but with some contribution of the functional promoter combination (rs11568817, rs130058). Associations with anger and hostility were not found in women. These findings extend our understanding of the genetic basis of anger and hostility by showing that newly characterized HTR1B haplotypes, particularly those with rs13212041, which modulates microRNA-mediated regulation of HTR1B expression, may have important implications for aggression-related phenotypes among young men.
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Ira , Hostilidade , Polimorfismo Genético , Receptor 5-HT1B de Serotonina/genética , Regiões 3' não Traduzidas , Adulto , Sequência de Bases , Primers do DNA , Genótipo , Haplótipos , Humanos , Masculino , Regiões Promotoras GenéticasRESUMO
RATIONALE: The nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate. OBJECTIVE: We developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate, and blood pressure. METHODS: Eighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 years old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions, in which they were randomly assigned to a saline infusion, or a 1 mg per 70-kg body weight dose of nicotine delivered over 1, 5, or 10 min at rates of 0.24, 0.048, or 0.024 µg/kg/s, respectively. RESULTS: Smoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1- and 5-min infusion, but not the 10-min infusion. Although the 1- and 5-min infusions reduced smoking urges to a similar extent, the 1-min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate, and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes. CONCLUSIONS: We have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~ 1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.
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Pressão Sanguínea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Frequência Cardíaca/efeitos dos fármacos , Nicotina/administração & dosagem , Fumantes/psicologia , Fumar Tabaco/psicologia , Adulto , Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/psicologia , Pressão Sanguínea/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Infusões Intravenosas , Masculino , Fumar Tabaco/fisiopatologia , Adulto JovemRESUMO
Alcohol use contributes to numerous diseases and injuries. The nervous system is affected by alcohol in diverse ways, though the molecular mechanisms of these effects are not clearly understood. Using human-induced pluripotent stem cells (iPSCs), we developed a neural cell culture model to identify the mechanisms of alcohol's effects. iPSCs were generated from fibroblasts and differentiated into forebrain neural cells cultures that were treated with 50 mM alcohol or sham conditions (same media lacking alcohol) for 7 days. We analyzed gene expression using total RNA sequencing (RNA-seq) for 34 samples derived from 10 subjects and for 10 samples from 5 subjects in an independent experiment that had intermittent exposure to the same dose of alcohol. We also analyzed genetic effects on gene expression and conducted a weighted correlation network analysis. We found that differentiated neural cell cultures have the capacity to recapitulate gene regulatory effects previously observed in specific primary neural tissues and identified 226 genes that were differentially expressed (FDR < 0.1) after alcohol treatment. The effects on expression included decreases in INSIG1 and LDLR, two genes involved in cholesterol homeostasis. We also identified a module of 58 co-expressed genes that were uniformly decreased following alcohol exposure. The majority of these effects were supported in independent alcohol exposure experiments. Enrichment analysis linked the alcohol responsive genes to cell cycle, notch signaling, and cholesterol biosynthesis pathways, which are disrupted in several neurological disorders. Our findings suggest that there is convergence between these disorders and the effects of alcohol exposure.
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Alcoolismo/genética , Etanol/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Células-Tronco Neurais/metabolismo , Adulto JovemRESUMO
Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer's disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.
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Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Colinérgicos/farmacologia , Colinérgicos/uso terapêutico , Sistema Colinérgico não Neuronal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Acetilcolina/farmacologia , Acetilcolina/uso terapêutico , Animais , HumanosRESUMO
Understanding the stimulatory effects of nicotine on cardiovascular function in humans is of great interest given the wide-spread use of different forms of combustible and smokeless products that deliver nicotine. An intravenous nicotine infusion procedure was used to evaluate factors associated with the acute heart rate (HR) response to nicotine (0.5â¯mg per 70â¯kg bodyweight) in a sample of 213 smokers. We tested for differential response to nicotine based on demographic characteristics (race [European American vs African America], sex, body mass index and age); a set of blood-based biomarkers (baseline nicotine, cotinine and cortisol levels and nicotine metabolite ratio); and a set of self-reported measures related to tobacco use. Nicotine infusion was first noted to increase HR approximately 10 beats per minute (95% CI: 7.8-12.3) one minute post-infusion, and 13 beats per minute (95% CI: 11.0-15.2) two minutes post-infusion. Higher cortisol, lower nicotine levels, higher nicotine metabolite ratio, being female and greater withdrawal symptoms were independently associated with a potentiated increase in HR 1 or 2â¯min after nicotine infusion. Factors associated with the acute HR effects of nicotine warrant further investigation given their potential to inform the development of nicotine delivery systems as tobacco harm reduction approaches for smokers.
Assuntos
Frequência Cardíaca/efeitos dos fármacos , Nicotina/farmacologia , Fumar Tabaco/metabolismo , Fumar Tabaco/fisiopatologia , Adulto , População Negra , Cotinina/metabolismo , Demografia , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Nicotina/efeitos adversos , Nicotina/metabolismo , Fatores de Risco , População BrancaRESUMO
AIM: We tested associations between HFE mutations and hepatitis B virus (HBV) infection. We also explored measures of total body iron status and their association with chronic HBV infection. METHODS: Serum measures of iron status and HFE mutations (C282Y, H63D, and S65C) were assessed in 344 Iranian patients with chronic HBV infection (214 asymptomatic carriers, 130 patients with chronic progressive liver disease [CPLD]) and 302 controls. RESULTS: Frequencies of HFE mutations did not differ between patients with chronic HBV infection and controls (C282Y: P=0.9, H63D: P= 0.8, S65C: P=0.9). By logistic regression, advanced hepatic fibrosis was associated with HFE H63D mutation (OR=13.1, P=0.006; 95% CI=2.0-84.1). Higher levels of serum ferritin and transferrin saturation were observed in patients with CPLD than in healthy controls (P=0.0001 and 0.01, respectively, adjusted for age and sex). None of the serum iron measures was related to liver fibrosis stage or necroinflammatory grade. CONCLUSION: Serum iron measures are associated with chronic progressive hepatitis B. Carriage of HFE mutations is not associated with the presence of chronic HBV infection or values of serum iron measures in this population, although HFE H63D is associated with more advanced hepatic fibrosis.
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To identify novel phenotypic associations related to Cytochrome P450 Family 2 Subfamily A Member 6 (CYP2A6), we investigated the human phenome in a total of 11,271 individuals. Initially, we conducted a phenome-wide association study in 3,401 nicotine-exposed elderly subjects considering 358 phenotypic traits. We identified a significant association between CYP2A6 rs113288603 and hearing loss symptoms (p = 5.75 × 10-5). No association was observed in a sample of 3,245 nicotine-unexposed individuals from the same discovery cohort, consistent with the conclusion that the finding is related to CYP2A6 involvement in nicotine metabolism. Consistent results were obtained (p < 0.1) in an independent sample of 2,077 nicotine-exposed elderly subjects, and similarly, no significance was observed in the nicotine-unexposed sample (n = 2,548) of the replication cohort. Additional supporting evidence for this association was provided by gene expression data: rs113288603 is associated with increased CYP2A6 expression in cerebellar hemispheres (p = 7.8 × 10-4). There is a well-known correlation between smoking and age-related hearing loss. Cigarette smoking is associated with structural changes in the brain and CYP2A6 mediates these changes. In this context, the regulatory role of rs113288603 in cerebellum appears to be consistent with the known involvement of this brain region in auditory function.
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Citocromo P-450 CYP2A6/genética , Perda Auditiva/genética , Polimorfismo de Nucleotídeo Único , Fumar Tabaco/efeitos adversos , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Fumar Tabaco/genéticaRESUMO
Substance use disorders (SUD) are a major contributor to disability and disease burden worldwide. Risk for developing SUDs is influenced by variation in the genome. Identifying the genetic variants that influence SUD risk may help us to understand the biological mechanisms for the disorders and improve treatments. Genome-wide association studies (GWAS) have been successful in identifying many regions of the genome associated with common human disorders. Here, findings from recent GWAS of SUDs that involve illicit substances will be reviewed. Several GWAS have been reported, including studies on opioid and stimulant use disorder (cocaine and methamphetamine). Several of these GWAS report associations that are biologically interesting and statistically robust. Replication of the associations in independent samples and functional studies to understand the basis for the statistical associations will be important next steps.
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Reducing the negative health effects caused by tobacco products continues to be a public health priority. The Family Smoking Prevention and Tobacco Control Act of 2009 gives the Food Drug Administration authority to pursue several new strategies, including regulating levels of nicotine and other ingredients in tobacco products. A nicotine reduction strategy proposed by Benowitz and Henningfield aims to reduce the nicotine content of tobacco products to an amount below a threshold that supports neither the development nor maintenance of addiction. Many factors must be considered to determine the viability and efficacy of this approach. For example, the policy should be based on precise information on the dose-dependent effects of nicotine on reinforcement and factors that contribute to individual differences in these effects. However, there have been few studies on these topics in humans. Here, we briefly review nicotine pharmacology and reinforcement then present several studies illustrating the application of intravenous (IV) nicotine delivery to study nicotine reinforcement in humans. We discuss how nicotine delivery by IV infusion may be uniquely suited for studying nicotine's dose-dependent effects, and how this can inform tobacco regulatory science to facilitate the development of effective tobacco control policies.
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Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Nicotina/administração & dosagem , Caracteres Sexuais , Tabagismo/psicologia , Administração Intravenosa , Adulto , Discriminação Psicológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , AutoadministraçãoRESUMO
OBJECTIVES: Menthol, a flavoring agent, is found in approximately 90% of cigarettes, but at much higher levels in menthol than non-menthol cigarettes. Menthol is reportedly included in cigarettes for its cooling and soothing effects, but also additional actions that affect smokers' receipt and processing of nicotine. In this study we investigated the response to short-term abstinence and acute nicotine delivery in menthol-preferring and non-menthol-preferring smokers. METHODS: Nicotine dependent participants (N = 134) participated in an intravenous nicotine delivery session following overnight smoking abstinence. Participants were intravenously administered a placebo and 2 escalating nicotine doses. We compare subjective and physiological responses to nicotine and smoking urges, withdrawal, and cognitive performance following overnight abstinence and post-nicotine between regular 'menthol' smokers and 'non-menthol' cigarette smokers. RESULTS: Relative to non-menthol-preferring smokers, menthol-preferring smokers re a smaller reduction in smoking urges from overnight abstinence baseline to post-nicotine end-of-session and rated less subjective differences between nicotine doses. CONCLUSIONS: Differences between menthol-preferring and non-menthol-preferring smokers' responses to abstinence or acute nicotine could reflect pre-existing individual differences that may have in initial development of menthol preferences, or could have arisen secondarily to pro use of menthol versus non-menthol cigarettes.