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Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.
Marees AT, Hammerschlag AR, Bastarache L, de Kluiver H, Vorspan F, van den Brink W, Smit DJ, Denys D, Gamazon ER, Li-Gao R, Breetvelt EJ, de Groot MCH, Galesloot TE, Vermeulen SH, Poppelaars JL, Souverein PC, Keeman R, de Mutsert R, Noordam R, Rosendaal FR, Stringa N, Mook-Kanamori DO, Vaartjes I, Kiemeney LA, den Heijer M, van Schoor NM, Klungel OH, Maitland-Van der Zee AH, Schmidt MK, Polderman TJC, van der Leij AR, Posthuma D, Derks EM
(2018) Drug Alcohol Depend 188: 94-101
MeSH Terms: Alcohol Drinking, Alcoholism, Cohort Studies, Exons, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Risk Factors, Tobacco Use, Tobacco Use Disorder
Show Abstract · Added May 26, 2018
BACKGROUND - Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.
METHODS - We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.
RESULTS - The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10) and rs8034191 (p = 6.31 × 10) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.
DISCUSSION - Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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15 MeSH Terms
Alcohol Use and Cardiovascular Disease Risk in Patients With Nonalcoholic Fatty Liver Disease.
VanWagner LB, Ning H, Allen NB, Ajmera V, Lewis CE, Carr JJ, Lloyd-Jones DM, Terrault NA, Siddique J
(2017) Gastroenterology 153: 1260-1272.e3
MeSH Terms: Adolescent, Adult, Age Factors, Alcohol Drinking, Binge Drinking, Chi-Square Distribution, Coronary Artery Disease, Cross-Sectional Studies, Echocardiography, Doppler, Female, Humans, Linear Models, Logistic Models, Longitudinal Studies, Male, Middle Aged, Multidetector Computed Tomography, Multivariate Analysis, Non-alcoholic Fatty Liver Disease, Odds Ratio, Prognosis, Protective Factors, Risk Assessment, Risk Factors, Time Factors, Underage Drinking, United States, Young Adult
Show Abstract · Added September 11, 2017
BACKGROUND & AIMS - Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). Moderate drinking (vs abstinence) is associated with lower risk of CVD in the general population. We assessed whether alcohol use is associated with CVD risk in patients with NAFLD.
METHODS - We analyzed data from participants in the Coronary Artery Risk Development in Young Adults longitudinal cohort study of 5115 black and white young adults, 18-30 years old, recruited from 4 cities in the United States from 1985 through 1986. Participants self-reported alcohol use at study entry and then again after 15, 20, and 25 years. At year 25 (2010-2011), participants underwent computed tomography examination of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking. Coronary artery calcification was defined as an Agatston score above 0. NAFLD was defined as liver attenuation <51 Hounsfield Units after exclusions. Drinkers reported 1-21 (men) or 1-14 (women) standard drinks/week at years 15, 20, or 25. Nondrinkers reported no alcohol use at years 15, 20, and 25.
RESULTS - Of the 570 participants with NAFLD (mean age, 50 years; 54% black; 46% female), 332 (58%) were drinkers; significantly higher proportions of drinkers were white, male, and with higher levels of education compared with nondrinkers (P < .05 for all). Higher proportions of drinkers had obesity, diabetes, and metabolic syndrome compared with nondrinkers (P < .01). There was no difference in liver attenuation between groups (P = .12). After multivariable adjustment, there was no association between alcohol use and CVD risk factors (diabetes, hypertension, hyperlipidemia) or subclinical CVD measures (coronary artery calcification, early transmitral velocity/late (atrial) transmitral velocity (E/A) ratio, global longitudinal strain).
CONCLUSIONS - In a population-based sample of individuals with NAFLD in midlife, prospectively assessed alcohol use is not associated with significant differences in risk factors for CVD or markers of subclinical CVD. In contrast to general population findings, alcohol use may not reduce the risk of CVD in patients with NAFLD.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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28 MeSH Terms
Patterns of prevalent HPV and STI co-infections and associated factors among HIV-negative young Western Cape, South African women: the EVRI trial.
Menezes LJ, Pokharel U, Sudenga SL, Botha MH, Zeier M, Abrahamsen ME, Glashoff RH, Engelbrecht S, Schim van der Loeff MF, van der Laan LE, Kipping S, Taylor D, Giuliano AR
(2018) Sex Transm Infect 94: 55-61
MeSH Terms: Adolescent, Alcohol Drinking, Chlamydia trachomatis, Coinfection, Female, Genotype, Gonorrhea, HIV Infections, HIV Seronegativity, Herpes Genitalis, Herpesvirus 2, Human, Humans, Medically Underserved Area, Papillomaviridae, Papillomavirus Infections, Papillomavirus Vaccines, Prevalence, Sexual Behavior, Sexual Partners, Sexually Transmitted Diseases, South Africa, Syphilis, Young Adult
Show Abstract · Added August 15, 2017
OBJECTIVE - To estimate the prevalence and describe the patterns of concurrent human papillomavirus (HPV) and STIs and associated factors among HIV-negative young Western Cape, South African women participating in the Efficacy of HPV Vaccine to Reduce HIV Infection (EVRI) trial.
METHODS - HIV-negative women aged 16-24 years old were enrolled in the EVRI trial (NCT01489527) and randomised to receive the licensed four-valent HPV vaccine or placebo. At study entry, participants were clinically evaluated for five STIs: herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis and disease-causing HPV genotypes (6/11/16/18/31/33/35/39/45/51/52/56/58/59/68). Demographic and sexual history characteristics were compared among women with STI co-infections, single infection and no infection using Pearson χ and Mann-Whitney tests. ORs were calculated to evaluate factors associated with STI co-infection prevalence.
RESULTS - Among 388 young women, STI co-infection prevalence was high: 47% had ≥2 concurrent STIs, 36% had a single STI and 17% had none of the five evaluated STIs. HPV/HSV-2 (26%) was the most prevalent co-infection detected followed by HPV/HSV-2/ (CT) (17%) and HPV/CT (15%). Co-infection prevalence was independently associated with alcohol use (adjusted OR=2.01, 95% CI 1.00 to 4.06) and having a sexual partner with an STI (adjusted OR=6.96, 95% CI 1.53 to 30.08).
CONCLUSIONS - Among high-risk young women from underserved communities such as in Southern Africa, a multicomponent prevention strategy that integrates medical and behavioural interventions targeting both men and women is essential to prevent acquisition of concurrent STI infections and consequent disease.
TRIAL REGISTRATION NUMBER - NCT01489527; Post-results.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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23 MeSH Terms
The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective.
Vranjkovic O, Pina M, Kash TL, Winder DG
(2017) Neuropharmacology 122: 100-106
MeSH Terms: Alcohol Drinking, Alcoholism, Animals, Drug-Seeking Behavior, Humans, Neural Pathways, Septal Nuclei
Show Abstract · Added March 26, 2019
The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components. Such recent developments are largely owed to methodological advances, which have made possible efforts previously deemed intractable, such as tracing of long-range cell-type specific projections and identifying functional efferent and afferent connections. In this review, we integrate earlier foundational work with more recent and advanced studies to construct a broad overview of the molecular neurocircuitry of the BNST in drug-associated behavior and affect. This article is part of the Special Issue entitled "Alcoholism".
Copyright © 2017 Elsevier Ltd. All rights reserved.
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Pregnancy Intention and Maternal Alcohol Consumption.
Pryor J, Patrick SW, Sundermann AC, Wu P, Hartmann KE
(2017) Obstet Gynecol 129: 727-733
MeSH Terms: Adult, Alcohol Drinking, Cohort Studies, Female, Health Promotion, Humans, Intention, Pregnancy, Pregnancy Trimester, First, Pregnancy, Unplanned, Preventive Health Services, Reproductive Behavior, Reproductive Health Services, Risk Reduction Behavior, Tennessee
Show Abstract · Added February 21, 2019
OBJECTIVE - To evaluate whether women planning a pregnancy are less likely to use alcohol in early pregnancy than those with unintended pregnancies.
METHODS - Right From the Start (2000-2012) is a prospective, community-based pregnancy cohort. Maternal demographic, reproductive, and behavioral data were collected in telephone interviews at enrollment (mean±standard deviation 48±13 days of gestation) and later in the first trimester (mean±standard deviation 85±21 days of gestation). Alcohol consumption characteristics were included in the interviews. We used logistic regression to investigate the association of pregnancy intention with alcohol use.
RESULTS - Among 5,036 women, 55% reported using alcohol in the first trimester with 6% continuing use at the first-trimester interview. Pregnancy was planned by 70% of participants. Alcohol use occurred in 55% and 56% of intended and unintended pregnancies, respectively (P=.32). Adjusting for confounders, women with intended pregnancies were 31% less likely to consume any alcohol in early pregnancy (adjusted odds ratio [OR] 0.69, 95% confidence interval [CI] 0.60-0.81) or binge drink (adjusted OR 0.68, 95% CI 0.54-0.86). Most women, regardless of intention, stopped or decreased alcohol consumption in early pregnancy.
CONCLUSION - The majority of women, irrespective of intention, stopped or decreased drinking after pregnancy recognition. This suggests promoting early pregnancy awareness could prove more effective than promoting abstinence from alcohol among all who could conceive.
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Alcohol Consumption and Incident Stroke Among Older Adults.
Cunningham SA, Mosher A, Judd SE, Matz LM, Kabagambe EK, Moy CS, Howard VJ
(2018) J Gerontol B Psychol Sci Soc Sci 73: 636-648
MeSH Terms: African Americans, Aged, Alcohol Drinking, European Continental Ancestry Group, Female, Humans, Incidence, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Sex Factors, Socioeconomic Factors, Stroke, United States
Show Abstract · Added February 18, 2017
Objectives - This study examines the relationship between alcohol consumption and incident stroke among older adults and tests whether alcohol consumption contributes to observed race and sex differences in stroke.
Method - Data are from a U.S. national cohort of black and white adults aged 45 and older, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Current and past drinking levels were reported at baseline (2003-2007). Participants who had never had a stroke were followed for adjudicated stroke events through September 2015 (n = 27,265). We calculated Cox proportional hazard models for stroke, adjusting for demographic, socioeconomic, behavioral, and health characteristics.
Results - Participants, mean age 64.7 years, consumed on average 2.2 drinks/week and experienced 1,140 first-time stroke events over median 9.1 years follow-up. Nondrinkers had a 12% higher risk of stroke than current drinkers; the risk of stroke among nondrinkers largely reflected high risks among past drinkers; these differences were explained by socioeconomic characteristics. Among current drinkers, light drinkers had significantly lower stroke risks than moderate drinkers after accounting for demographic, socioeconomic, behavioral, and health characteristics. Implications of alcohol did not differ between blacks and whites but did differ by sex: Especially among women, nondrinkers, and specifically past drinkers, had higher risks; these differences were largely explained by health characteristics and behaviors. Alcohol did not explain race and sex differences in stroke incidence.
Discussion - Among older adults, those who used to, but no longer, drink had higher risks of stroke, especially among women; current light drinkers had the lowest risk of stroke.
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Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit.
Radke AK, Jury NJ, Delpire E, Nakazawa K, Holmes A
(2017) Alcohol 58: 47-51
MeSH Terms: Alcohol Drinking, Animals, Cerebral Cortex, Choice Behavior, Ethanol, Female, Gene Deletion, Interneurons, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Protein Subunits, Receptors, N-Methyl-D-Aspartate
Show Abstract · Added May 3, 2017
N-Methyl-d-aspartate receptors (NMDAR) are involved in the regulation of alcohol drinking, but the contribution of NMDAR subunits located on specific neuronal populations remains incompletely understood. The current study examined the role of GluN2B-containing NMDARs expressed on cortical principal neurons and cortical interneurons in mouse ethanol drinking. Consumption of escalating concentrations of ethanol was measured in mice with GluN2B gene deletion in either cortical principal neurons (GluN2B) or interneurons (GluN2B), using a two-bottle choice paradigm. Results showed that GluN2B, but not GluN2B, mice consumed significantly less ethanol, at relatively high concentrations, than non-mutant controls. In a second paradigm in which mice were offered a 15% ethanol concentration, without escalation, GluN2B mice were again no different from controls. These findings provide novel evidence for a contribution of interneuronal GluN2B-containing NMDARs in the regulation of ethanol drinking.
Copyright © 2016 Elsevier Inc. All rights reserved.
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Adherence to Cancer Prevention Guidelines and Cancer Risk in Low-Income and African American Populations.
Warren Andersen S, Blot WJ, Shu XO, Sonderman JS, Steinwandel MD, Hargreaves MK, Zheng W
(2016) Cancer Epidemiol Biomarkers Prev 25: 846-53
MeSH Terms: Adult, African Americans, Aged, Alcohol Drinking, Body Weight, Diet, Exercise, Female, Healthy Lifestyle, Humans, Incidence, Male, Middle Aged, Neoplasms, Poverty, Practice Guidelines as Topic, Smoking, United States
Show Abstract · Added April 28, 2016
BACKGROUND - The American Cancer Society (ACS) publishes behavioral guidelines for cancer prevention, including standards on body weight, physical activity, nutrition, alcohol, and tobacco use. The impact of these guidelines has been rarely studied in low-income and African American populations.
METHODS - The study included 61,098 racially diverse, mainly low-income adults who participated in the Southern Community Cohort Study and were followed for a median of 6 years. Cox models were used to estimate HRs for cancer incidence associated with behaviors and with an ACS physical activity/nutrition 0-to-4 compliance score indicating the number of body weight, physical activity, healthy eating, and alcohol guidelines met.
RESULTS - During the study period, 2,240 incident cancers were identified. Significantly lower cancer incidence was found among never smokers and non/moderate alcohol drinkers, but not among those meeting guidelines for obesity, physical activity, and diet. The ACS compliance score was inversely associated with cancer risk among the 25,509 participants without baseline chronic disease. HRs for cancer incidence among those without baseline chronic diseases and who met one, two, three, or four guidelines versus zero guidelines were 0.93 (95% confidence intervals, 0.71-1.21), 0.85 (0.65-1.12), 0.70 (0.51-0.97), and 0.55 (0.31-0.99), respectively. Associations were consistent in analyses stratified by sex, race, household income, and smoking status.
CONCLUSIONS - Meeting the ACS smoking and body weight/physical activity/dietary/alcohol guidelines for cancer prevention is associated with reductions in cancer incidence in low-income and African American populations.
IMPACT - This study provides strong evidence supporting lifestyle modification to lower cancer incidence in these underserved populations. Cancer Epidemiol Biomarkers Prev; 25(5); 846-53. ©2016 AACR.
©2016 American Association for Cancer Research.
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18 MeSH Terms
Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking.
Holleran KM, Wilson HH, Fetterly TL, Bluett RJ, Centanni SW, Gilfarb RA, Rocco LE, Patel S, Winder DG
(2016) Neuropsychopharmacology 41: 2062-71
MeSH Terms: Affect, Alcohol Drinking, Animals, Behavior, Animal, Benzodioxoles, Depression, Endocannabinoids, Ethanol, Excitatory Amino Acid Antagonists, Female, Ketamine, Mice, Inbred C57BL, Monoacylglycerol Lipases, Piperidines
Show Abstract · Added March 14, 2018
Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders.
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Dietary magnesium, calcium:magnesium ratio and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma: a population-based case-control study.
Dai Q, Cantwell MM, Murray LJ, Zheng W, Anderson LA, Coleman HG, FINBAR study group
(2016) Br J Nutr 115: 342-50
MeSH Terms: Adenocarcinoma, Aged, Alcohol Drinking, Barrett Esophagus, Body Mass Index, Calcium, Dietary, Case-Control Studies, Diet, Diet Records, Educational Status, Esophageal Neoplasms, Esophagitis, Peptic, Humans, Ireland, Magnesium, Middle Aged, Northern Ireland, Odds Ratio, Risk Factors, Smoking
Show Abstract · Added May 6, 2016
Evidence suggests a role of Mg and the ratio of Ca:Mg intakes in the prevention of colonic carcinogenesis. The association between these nutrients and oesophageal adenocarcinoma - a tumour with increasing incidence in developed countries and poor survival rates - has yet to be explored. The aim of this investigation was to explore the association between Mg intake and related nutrients and risk of oesophageal adenocarcinoma and its precursor conditions, Barrett's oesophagus and reflux oesophagitis. This analysis included cases of oesophageal adenocarcinoma (n 218), Barrett's oesophagus (n 212), reflux oesophagitis (n 208) and population-based controls (n 252) recruited between 2002 and 2005 throughout the island of Ireland. All the subjects completed a 101-item FFQ. Unconditional logistic regression analysis was applied to determine odds of disease according to dietary intakes of Mg, Ca and Ca:Mg ratio. After adjustment for potential confounders, individuals consuming the highest amounts of Mg from foods had significant reductions in the odds of reflux oesophagitis (OR 0·31; 95 % CI 0·11, 0·87) and Barrett's oesophagus (OR 0·29; 95 % CI 0·12, 0·71) compared with individuals consuming the lowest amounts of Mg. The protective effect of Mg was more apparent in the context of a low Ca:Mg intake ratio. No significant associations were observed for Mg intake and oesophageal adenocarcinoma risk (OR 0·77; 95 % CI 0·30, 1·99 comparing the highest and the lowest tertiles of consumption). In conclusion, dietary Mg intakes were inversely associated with reflux oesophagitis and Barrett's oesophagus risk in this Irish population.
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20 MeSH Terms