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1.
J Psychiatry Neurosci ; 44(6): 1-11, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31490055

RESUMO

Background: Phenotypic heterogeneity and complicated gene­environment interplay in etiology are among the primary factors that hinder the identification of genetic variants associated with cocaine use disorder. Methods: To detect novel genetic variants associated with cocaine use disorder, we derived disease traits with reduced phenotypic heterogeneity using cluster analysis of a study sample (n = 9965). We then used these traits in genome-wide association tests, performed separately for 2070 African Americans and 1570 European Americans, using a new mixed model that accounted for the moderating effects of 5 childhood environmental factors. We used an independent sample (918 African Americans, 1382 European Americans) for replication. Results: The cluster analysis yielded 5 cocaine use disorder subtypes, of which subtypes 4 (n = 3258) and 5 (n = 1916) comprised heavy cocaine users, had high heritability estimates (h2 = 0.66 and 0.64, respectively) and were used in association tests. Seven of the 13 identified genetic loci in the discovery phase were available in the replication sample. In African Americans, rs114492924 (discovery p = 1.23 × E−8), a single nucleotide polymorphism in LINC01411, was replicated in the replication sample (p = 3.63 × E−3). In a meta-analysis that combined the discovery and replication results, 3 loci in African Americans were significant genome-wide: rs10188036 in TRAK2 (p = 2.95 × E−8), del-1:15511771 in TMEM51 (p = 9.11 × E−10) and rs149843442 near LPHN2 (p = 3.50 × E−8). Limitations: Lack of data prevented us from replicating 6 of the 13 identified loci. Conclusion: Our results demonstrate the importance of considering phenotypic heterogeneity and gene­environment interplay in detecting genetic variations that contribute to cocaine use disorder, because new genetic loci have been identified using our novel analytic method.

3.
AIDS Behav ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31435887

RESUMO

We contrast three types of abstinence: quit after alcohol associated problems (Q-AP), quit for other reasons (Q-OR), and lifetime abstainer (LTA). We summarized the characteristics of people living with HIV (PLWH), and matched uninfected individuals, by levels of alcohol use and types of abstinence. We then identified factors that differentiate abstinence and determined whether the association with an alcohol biomarker or a genetic polymorphism is improved by differentiating abstinence. Among abstainers, 34% of PLWH and 38% of uninfected were Q-AP; 53% and 53% were Q-OR; and 12% and 10% were LTA. Logistic regression models found smoking, alcohol, cocaine, and hepatitis C increased odds of Q-AP, whereas smoking and marijuana decreased odds of LTA. Differentiating types of abstinence improved association. Q-APs and LTAs can be readily differentiated by an alcohol biomarker and genetic polymorphism. Differentiating type of abstinence may enhance understanding of alcohol health effects.

4.
Alcohol Clin Exp Res ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31436886

RESUMO

BACKGROUND: Precision medicine aims to identify those patients who will benefit the most from specific treatments. Recent work found large effects of naltrexone among "reward drinkers," defined as individuals who drink primarily for the rewarding effects of alcohol. This study sought to replicate and extend these recent findings by examining whether the desire to drink mediated the effect of naltrexone among reward drinkers. METHODS: We conducted a secondary analysis of a 12-week randomized clinical trial of daily or targeted naltrexone among problem drinkers (n = 163), with a focus on 86 individuals (n = 45 naltrexone and n = 41 placebo) who received daily medication. Interactive voice response technology was used to collect daily reports of drinking and desire to drink. Factor mixture models were used to derive reward and relief phenotypes. Moderation analyses were used to evaluate naltrexone effects, with phenotype as a moderator variable. Multilevel mediation tested average desire to drink as a mediator. RESULTS: Results indicated 4 phenotypes: low reward/low relief; low reward/high relief; high reward/low relief; and high reward/high relief. There was an interaction between the high reward/low relief subgroup (n = 10) and daily naltrexone versus placebo on drinks per drinking day (DPDD; p = 0.03), percent heavy drinking days (p = 0.004), and daily drinking (p = 0.02). As compared to placebo, individuals in the high reward/low relief phenotype who received daily naltrexone had significantly fewer DPDD (Cohen's d = 2.05) and had a lower proportion of heavy drinking days (Cohen's d = 1.75). As hypothesized, reductions in average desire to drink mediated the effect of naltrexone on average daily drinking among the high reward/low relief drinkers (moderated mediation effect: p = 0.029). CONCLUSIONS: This theory-driven study replicates the empirical finding that naltrexone is particularly efficacious among high reward/low relief drinkers. Our study brings the field a step closer to the potential of using a precision medicine approach to treating alcohol use disorder.

5.
Depress Anxiety ; 36(9): 834-845, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385647

RESUMO

BACKGROUND: Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. METHODS: We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of ε4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of ε4 carrier status. RESULTS: APOE ε4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. ε4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with ε4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59). CONCLUSIONS: APOE ε4 allele carriers with PTSD have substantially greater cognitive difficulties than ε4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.

6.
Addict Biol ; : e12811, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362332

RESUMO

The United States is experiencing the worst opioid overdose (OpOD) crisis in its history. We carried out a genome-wide association study on OpOD severity among 3 477 opioid-exposed individuals, 1 019 of whom experienced OpODs, including 2 032 European Americans (EAs) (653 overdose cases), and 1 445 African Americans (AAs) (366 overdose cases). Participants were scored 1 to 4 based on their reported overdose status and the number of times that medical treatment was required. Genome-wide association study (GWAS) of EAs and AAs separately resulted in two genome-wide significant (GWS) signals in AAs but none in EAs. The first signal was represented by three closely mapped variants (rs115208233, rs116181528, and rs114077267) located near mucolipin 1 (MCOLN1) and patatin-like phospholipase domain containing 6 (PNPLA6), and the other signal was represented by rs369098800 near dead-box helicase 18 (DDX18). There were no additional GWS signals in the trans-population meta-analysis, so that post-GWAS analysis focused on these loci. In network analysis, MCOLN1 was coexpressed with PNPLA6, but only MCOLN1-associated genes were enriched in functional categories relevant to OpOD, including calcium and cation channel activities; no enrichment was observed for PNPLA6-associated genes. Drug repositioning analysis was carried out in the connectivity map (CMap) database for MCOLN1 (PNPLA6 was not available in CMap) and showed that the opioid agonist drug-induced expression profile is similar to that of MCOLN1 overexpression and yielded the highest-ranked expression profile of 83 drug classes. Thus, MCOLN1 may be a risk gene for OpOD, but replication is needed. This knowledge could be helpful in the identification of drug targets for preventing OpOD.

7.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

8.
AIDS Behav ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31317364

RESUMO

A better understanding of predisposition to transition to high-dose, long-term opioid therapy after initial opioid receipt could facilitate efforts to prevent opioid use disorder (OUD). We extracted data on 69,268 patients in the Veterans Aging Cohort Study who received any opioid prescription between 1998 and 2015. Using latent growth mixture modelling, we identified four distinguishable dose trajectories: low (53%), moderate (29%), escalating (13%), and rapidly escalating (5%). Compared to low dose trajectory, those in the rapidly escalating dose trajectory were proportionately more European-American (59% rapidly escalating vs. 38% low); had a higher prevalence of HIV (31% vs. 29%) and hepatitis C (18% vs. 12%); and during follow-up, had a higher incidence of OUD diagnoses (13% vs. 3%); were hospitalised more often [18.1/100 person-years (PYs) vs. 12.5/100 PY]; and had higher all-cause mortality (4.7/100 PY vs. 1.8/100 PY, all p < 0.0001). These measures can potentially be used in future prevention research, including genetic discovery.

9.
Drug Alcohol Depend ; 201: 16-22, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174140

RESUMO

BACKGROUND: To provide information on the clinical relevance of a reduction in the World Health Organization (WHO) drinking risk categories, we examined their relationship to an important indicator of how individuals feel and function: drug use disorders (DUDs), i.e., those involving substances other than alcohol. METHOD: Current drinkers in a U.S. national survey (n = 22,005) were interviewed in 2001-02 and re-interviewed 3 years later. WHO drinking risk levels and DSM-IV-defined DUD were assessed at both waves. The relationship of changes in WHO drinking risk levels to the presence of DUD were examined using adjusted odds ratios (aOR). RESULTS: At Wave 1, 2.5% of respondents were WHO very-high-risk drinkers, and 2.5%, 4.8%, and 90.2% were high-risk, moderate-risk, and low-risk drinkers, respectively. Among Wave 1 very-high-risk drinkers, significantly lower odds of DUD at Wave 2 were predicted by reductions in WHO risk levels of one, two or three levels (aOR = 0.15, 0.01, 0.24, respectively; all p-values <.0001). Among participants who initially were drinking at lower risk levels, reductions in drinking or abstinence were generally associated with significantly lower odds of DUD, although the results were less consistent. CONCLUSIONS: Among very-high-risk drinkers, reduction in the WHO drinking risk categories were associated with lower risk of a DUD. These results add to findings indicating that reductions in WHO drinking risk levels are a meaningful indicator of how individuals feel and function and could therefore serve as informative outcomes in alcohol clinical trials. WHO risk levels can also guide treatment goals and clinical recommendations on drinking reduction.

10.
Expert Opin Drug Metab Toxicol ; 15(7): 553-564, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162983

RESUMO

Introduction: Alcohol use disorder (AUD) is highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated. The low rate of utilization of medications with demonstrated (albeit modest) efficacy is particularly noteworthy. One approach to increasing the utility and safety of available medications is to use a precision medicine approach, which seeks to identify patients for whom specific medications are likely to be most efficacious and have the fewest adverse effects. Areas Covered: We review the literature on the pharmacogenetics of AUD treatment using both approved and off-label medications. We cover both laboratory studies and clinical trials, highlighting valuable mechanistic insights and underscoring the potential value of precision-based care for AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, a precision medicine approach is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data provides important opportunities to develop this area of research.


Assuntos
Alcoolismo/tratamento farmacológico , Farmacogenética , Medicina de Precisão/métodos , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/efeitos adversos , Alcoolismo/genética , Alcoolismo/fisiopatologia , Humanos , Uso Off-Label
11.
Biol Psychiatry ; 86(5): 365-376, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151762

RESUMO

BACKGROUND: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS: We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS: ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS: The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

12.
Epigenomics ; 11(7): 739-749, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140863

RESUMO

Aim: Salivary miRNA can be easily accessible biomarkers of alcohol dependence (AD). Materials & methods: The miRNA transcriptome in the saliva of 56 African-Americans (AAs; 28 AD patients/28 controls) and 64 European-Americans (EAs; 32 AD patients/32 controls) was profiled using small RNA sequencing. Differentially expressed miRNAs were identified. Salivary miRNAs were used to predict the AD presence using machine learning with Random Forests. Results: Seven miRNAs were differentially expressed in AA AD patients, and five miRNAs were differentially expressed in EA AD patients. The AD prediction accuracy based on top five miRNAs (ranked by Gini index) was 79.1 and 72.2% in AAs and EAs, respectively. Conclusion: This study provided the first evidence that salivary miRNAs are AD biomarkers.

13.
Nat Commun ; 10(1): 2275, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101824

RESUMO

The original version of this Article omitted the following from the Acknowledgements: 'Supported by the Mental Illness Research, Education and Clinical Center of the Veterans Integrated Service Network 4 of the Department of Veterans Affairs.' This has now been corrected in both the PDF and HTML versions of the Article.

14.
Nicotine Tob Res ; 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063550

RESUMO

INTRODUCTION: Smokers who use opioids smoke more cigarettes per day (CPD) than non-opioid users, which could be due to the effects of opioids on nicotine metabolism. Moreover, nicotine metabolism increases during pregnancy, potentially making quitting more difficult for pregnant smokers. We examined nicotine metabolism and its association with opioid use (OU) and CPD in pregnant smokers. METHODS: We recruited pregnant women who smoked ≥ 5 CPD for a clinical trial of smoking cessation. Plasma nicotine metabolite ratio (3-hydroxycotinine (3HC)/cotinine) (NMR)-a biomarker of nicotine metabolism-OU (involving methadone, buprenorphine, fentanyl, oxycodone, or tramadol), and CPD were assessed at baseline. We used linear regression to examine the associations between log-transformed NMR, OU, and CPD, adjusting for race/ethnicity and menthol smoking. RESULTS: Among 129 pregnant smokers, 25 (19%) were opioid users; most were maintained on methadone (n=14). Compared to non-OU smokers, OU smokers had higher median CPD (10.0 vs. 7.0, p=0.0007), serum 3HC (81.0 vs. 42.0 ng/mL, p=0.0001), and NMR (0.63 vs. 0.43, p<0.0001). Additionally, methadone-maintained smokers had a higher median NMR than non-OU smokers (0.66 vs. 0.43, p=0.0004). Adjusting for covariates, log-transformed NMR was greater in OU smokers (p=0.012), specifically methadone-maintained smokers (p=0.024), than non-OU smokers. CONCLUSIONS: Our preliminary results show that OU is associated with a higher NMR in pregnant smokers. A larger study sample is needed to replicate this finding, examine potential mechanisms, and determine its clinical significance. IMPLICATIONS: Among pregnant smokers, we observed that nicotine metabolism was significantly faster among opioid users-the majority of whom were on methadone maintenance-compared to non-users, which could have implications for smoking cessation. Further studies are needed to replicate this finding, evaluate potential mechanisms, and determine its clinical significance.

15.
Addiction ; 114(9): 1547-1555, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31077485

RESUMO

BACKGROUND AND AIMS: Studies of the efficacy of gabapentin for treating alcohol use disorder (AUD) have yielded mixed findings. The aims of our study were to estimate gabapentin's effects on six alcohol-related outcomes, test potential moderators, examine publication bias and evaluate the quality of the studies. METHODS: Meta-analysis of placebo-controlled randomized controlled trials (RCTs). Using PubMed and ClinicalTrials.gov, we selected RCTs of gabapentin's effects on alcohol consumption or a biochemical correlate of it, excluding studies limited to other primary outcomes or that combined gabapentin with other medications. We assessed study quality and used a random-effects model to analyze each outcome measure and the Egger regression test and funnel plots to assess publication bias. RESULTS: We identified seven RCTs of gabapentin that met study criteria. The quality of the studies overall was good, and there was no evidence of publication bias. Four to seven studies contributed to the analysis of the six outcome measures. For all outcome measures the effect estimates were in a direction that favored gabapentin over placebo. However, only for percentage of heavy drinking days was there good evidence of a benefit (g = -0.64, 95% confidence interval = -1.22 to -0.06). CONCLUSIONS: Although gabapentin appears to be more efficacious than placebo in treating AUD, the only measure on which the analysis clearly favors the active medication is percentage of heavy drinking days. Additional studies are needed to define more clearly the role of gabapentin in AUD treatment.

16.
Alcohol Clin Exp Res ; 43(5): 979-987, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30951210

RESUMO

BACKGROUND: Reductions in the World Health Organization (WHO) risk drinking levels have been proposed as an alternative primary outcome for alcohol clinical trials. Yet, little is known about whether reductions in WHO risk drinking levels can be maintained over time. The current study examined whether reductions in WHO risk drinking levels were maintained for up to 1 year following treatment, and whether reductions over time were associated with improvements in functioning. METHODS: Secondary data analysis of individuals with alcohol dependence (n = 1,226) enrolled in the COMBINE study, a multisite, randomized, placebo-controlled clinical trial. Logistic regression was used to examine the maintenance of end-of-treatment WHO risk level reductions and WHO risk level reductions at the 1-year follow-up. Repeated-measures mixed models were used to examine the association between WHO risk level reductions and functional outcomes over time. RESULTS: Achieving at least a 1- or 2-level reduction in risk by the end of treatment was significantly associated with WHO risk level reductions at the 1-year follow-up assessment (p < 0.001). Among individuals who achieved at least a 1-level reduction by the end of treatment, 85.5% reported at least a 1-level reduction at the 1-year follow-up. Among individuals who achieved at least a 2-level reduction by the end of treatment, 77.8% reported at least a 2-level reduction at the 1-year follow-up. WHO risk level reductions were associated with significantly lower alcohol consumption, better physical health (p < 0.01), and fewer alcohol-related consequences (p < 0.001) up to 1 year following treatment. CONCLUSIONS: One- and 2-level reductions in WHO risk levels during alcohol treatment were maintained after treatment and associated with better functioning over time. These findings support the use of the WHO risk level reductions as an outcome measure that reflects clinically significant improvement in how individuals seeking treatment for alcohol use disorder feel and function.

17.
Nat Commun ; 10(1): 1499, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940813

RESUMO

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
Sci Rep ; 9(1): 4660, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30874594

RESUMO

There is currently an epidemic of opioid use, overdose, and dependence in the United States. Although opioid dependence (OD) is more prevalent in men, opioid relapse and fatal opioid overdoses have recently increased at a higher rate among women. Epigenetic mechanisms have been implicated in the etiology of OD, though most studies to date have used candidate gene approaches. We conducted the first epigenome-wide association study (EWAS) of OD in a sample of 220 European-American (EA) women (140 OD cases, 80 opioid-exposed controls). DNA was derived from whole blood samples and EWAS was implemented using the Illumina Infinium HumanMethylationEPIC array. To identify differentially methylated CpG sites, we performed an association analysis adjusting for age, estimates of cell proportions, smoking status, and the first three principal components to correct for population stratification. After correction for multiple testing, association analysis identified three genome-wide significant differentially methylated CpG sites mapping to the PARG, RERE, and CFAP77 genes. These genes are involved in chromatin remodeling, DNA binding, cell survival, and cell projection. Previous genome-wide association studies have identified RERE risk variants in association with psychiatric disorders and educational attainment. DNA methylation age in the peripheral blood did not differ between OD subjects and opioid-exposed controls. Our findings implicate epigenetic mechanisms in OD and, if replicated, identify possible novel peripheral biomarkers of OD that could inform the prevention and treatment of the disorder.

19.
Alcohol Clin Exp Res ; 43(6): 1244-1253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30912860

RESUMO

BACKGROUND: Insomnia is highly prevalent in individuals recovering from alcohol dependence (AD) and increases their risk of relapse. Two studies evaluating cognitive behavior therapy for insomnia (CBT-I) have demonstrated its efficacy in non-Veterans recovering from AD. The aim of this study was to extend these findings in an 8-week trial of CBT-I in Veterans. METHODS: Veterans recovering from AD were randomly assigned to 8 weeks of treatment with CBT-I (N = 11) or a Monitor-Only (MO; N = 11) condition and were evaluated 3 (N = 21/22) and 6 months posttreatment (N = 18/22). The primary outcome measure was the Insomnia Severity Index (ISI) score. Secondary outcome measures were sleep diary measures, percent days abstinent (PDA), and scores on the Dysfunctional Beliefs and Attitudes About Sleep Scale (DBAS), Sleep Hygiene Index (SHI), Penn Alcohol Craving Scale (PACS), Quick Inventory of Depressive Symptoms (QIDS), State-Trait Anxiety Inventory-Trait (STAI-T) scale, and Short Form 12-item (SF-12). Mixed-effects regression models, adjusted for race, evaluated differences in outcomes between the groups over a 6-month period (clinicaltrials.gov identifier = NCT01603381). RESULTS: Subjects were male, aged 54.5 (SD = 6.9) years, and had 26.4 (SD = 26.3) days of abstinence before their baseline evaluation. CBT-I produced a significantly greater improvement in model-based estimates than MO (mean change at 6 months compared to their baseline) for ISI, sleep latency from a daily sleep diary, DBAS mean score, and SHI total score. PDA and QIDS improved over time, but there was no difference between the groups. PACS, STAI-T, or SF-12 scale did not show any improvement from their baseline scores. CONCLUSIONS: CBT-I treatment demonstrated substantial efficacy in reducing insomnia, associated negative cognitions, and improving sleep hygiene in Veterans during early recovery, though it did not reduce drinking behavior.

20.
Drug Alcohol Depend ; 197: 228-235, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30852375

RESUMO

BACKGROUND: Non-abstinent drinking reductions that predict improvement in how individuals feel or function, such as the World Health Organization (WHO) drinking risk levels, may be useful outcomes in clinical trials for alcohol use disorders (AUD). METHODS: Current drinkers in a U.S. national survey (n = 22,005) were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (Wave 2). WHO drinking risk levels, a 4- level categorization system (very-high-risk, high-risk, moderate-risk, and low-risk drinkers) defined using estimated mean ethanol consumption (grams) per day in the prior 12 months, and DSM-IV depressive and anxiety disorders were assessed at both waves. Logistic regression was used to produce adjusted odds ratios (aOR) testing the associations of changes between Wave 1 and Wave 2 WHO risk levels to the presence or persistence of depression and/or anxiety disorder by each initial Wave 1 risk level. RESULTS: Among Wave 1 very-high-risk drinkers, lower odds of depression and/or anxiety disorders at Wave 2 were predicted by reductions in WHO risk levels of one-, two- or three-levels (aOR = 0.42, 0.37, 0.67, p-values 0.04-<.0001), as was the persistence of depression and/or anxiety disorders among those with such disorders at Wave 1 (aOR = 0.37, 0.29, 0.51, p-values .03-<.0001). Results were less consistent for participants initially drinking at lower risk levels. CONCLUSIONS: Among very-high-risk drinkers, reductions in the WHO drinking risk categories were associated with lower risk of depression and/or anxiety disorders. These results add to findings indicating reductions in WHO risk levels are a meaningful indicator of how individuals feel and function.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Transtornos de Ansiedade/epidemiologia , Transtorno Depressivo/epidemiologia , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Transtornos de Ansiedade/psicologia , Transtorno Depressivo/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco/normas , Estados Unidos/epidemiologia , Organização Mundial da Saúde , Adulto Jovem
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