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Merzah M, Natae S, Sándor J, Fiatal S. Single Nucleotide Variants (SNVs) of the Mesocorticolimbic System Associated with Cardiovascular Diseases and Type 2 Diabetes: A Systematic Review. Genes (Basel) 2024; 15:109. [PMID: 38254998 PMCID: PMC10815084 DOI: 10.3390/genes15010109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
The mesocorticolimbic (MCL) system is crucial in developing risky health behaviors which lead to cardiovascular diseases (CVDs) and type 2 diabetes (T2D). Although there is some knowledge of the MCL system genes linked to CVDs and T2D, a comprehensive list is lacking, underscoring the significance of this review. This systematic review followed PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The PubMed and Web of Science databases were searched intensively for articles related to the MCL system, single nucleotide variants (SNVs, formerly single nucleotide polymorphisms, SNPs), CVDs, T2D, and associated risk factors. Included studies had to involve a genotype with at least one MCL system gene (with an identified SNV) for all participants and the analysis of its link to CVDs, T2D, or associated risk factors. The quality assessment of the included studies was performed using the Q-Genie tool. The VEP and DAVID tools were used to annotate and interpret genetic variants and identify enriched pathways and gene ontology terms associated with the gene list. The review identified 77 articles that met the inclusion criteria. These articles provided information on 174 SNVs related to the MCL system that were linked to CVDs, T2D, or associated risk factors. The COMT gene was found to be significantly related to hypertension, dyslipidemia, insulin resistance, obesity, and drug abuse, with rs4680 being the most commonly reported variant. This systematic review found a strong association between the MCL system and the risk of developing CVDs and T2D, suggesting that identifying genetic variations related to this system could help with disease prevention and treatment strategies.
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Affiliation(s)
- Mohammed Merzah
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (M.M.)
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
| | - Shewaye Natae
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (M.M.)
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
| | - János Sándor
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (M.M.)
- ELKH-DE Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Szilvia Fiatal
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (M.M.)
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Yang Z, Chen J, Han H, Wang Y, Shi X, Zhang B, Mao Y, Li AN, Yuan W, Yao J, Li MD. Single nucleotide polymorphisms rs148582811 regulates its host gene ARVCF expression to affect nicotine-associated hippocampus-dependent memory. iScience 2023; 26:108335. [PMID: 38025780 PMCID: PMC10679859 DOI: 10.1016/j.isci.2023.108335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/24/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Although numerous susceptibility loci are nominated for nicotine dependence (ND), no report showed any association of ARVCF with ND. Through genome-wide sequencing analysis, we first identified genetic variants associated nominally with ND and then replicated them in an independent sample. Of the six replicated variants, rs148582811 in ARVCF located in the enhancer-associated marker peak is attractive. The effective-median-based Mendelian randomization analysis indicated that ARVCF is a causal gene for ND. RNA-seq analysis detected decreased ARVCF expression in smokers compared to nonsmokers. Luciferase reporter assays indicated that rs148582811 and its located DNA fragment allele-specifically regulated ARVCF expression. Immunoprecipitation analysis revealed that transcription factor X-ray repair cross-complementing protein 5 (XRCC5) bound to the DNA fragment containing rs148582811 and allele-specifically regulated ARVCF expression at the mRNA and protein levels. With the Arvcf knockout mouse model, we showed that Arvcf deletion not only impairs hippocampus-dependent learning and memory, but also alleviated nicotine-induced memory deficits.
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Affiliation(s)
- Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Joint Institute of Smoking and Health, Kunming, Yunnan 650024, China
| | - Jiali Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yan Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Xiaoqiang Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Bin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Ying Mao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Andria N. Li
- Vanderbilt University School of Medicine, Nashville, TN 37240, USA
| | - Wenji Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Jianhua Yao
- Joint Institute of Smoking and Health, Kunming, Yunnan 650024, China
| | - Ming D. Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Research Center for Air Pollution and Health, Zhejiang University, Hangzhou 310058, China
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Goud TJ. Epigenetic and Long-Term Effects of Nicotine on Biology, Behavior, and Health. Pharmacol Res 2023; 192:106741. [PMID: 37149116 DOI: 10.1016/j.phrs.2023.106741] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 05/08/2023]
Abstract
Tobacco and nicotine use are associated with disease susceptibility and progression. Health challenges associated with nicotine and smoking include developmental delays, addiction, mental health and behavioral changes, lung disease, cardiovascular disease, endocrine disorders, diabetes, immune system changes, and cancer. Increasing evidence suggests that nicotine-associated epigenetic changes may mediate or moderate the development and progression of a myriad of negative health outcomes. In addition, nicotine exposure may confer increased lifelong susceptibility to disease and mental health challenges through alteration of epigenetic signaling. This review examines the relationship between nicotine exposure (and smoking), epigenetic changes, and maladaptive outcomes that include developmental disorders, addiction, mental health challenges, pulmonary disease, cardiovascular disease, endocrine disorders, diabetes, immune system changes, and cancer. Overall, findings support the contention that nicotine (or smoking) associated altered epigenetic signaling is a contributing factor to disease and health challenges.
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Affiliation(s)
- Thomas J Goud
- Department of Biobehavioral Health, The Pennsylvania State University, Penn State University, University Park, PA, USA.
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Neurobiology and Mechanisms of Nicotine Addiction. Respir Med 2023. [DOI: 10.1007/978-3-031-24914-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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Associations between the COMT rs4680 Gene Polymorphism and Personality Dimensions and Anxiety in Patients with a Diagnosis of Other Stimulants Dependence. Genes (Basel) 2022; 13:genes13101768. [PMID: 36292653 PMCID: PMC9601926 DOI: 10.3390/genes13101768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/16/2022] [Accepted: 09/27/2022] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Research on the hypodopaminergic hypothesis of addictions showed that hypodopaminergic activity in males predicted the number of drugs used and is associated with drug-seeking behavior. Variant alleles may cause hypodopaminergic functioning as a result of the reduced density of dopamine receptors, decreased response to dopamine, increased dopamine clearance or metabolism in the reward system. The catechol-O-methyltransferase (COMT) is involved in the metabolism of dopamine. Personality traits may mediate the genetic predisposition to substance use disorders additively by various motivations associated with reward-seeking and regulating negative emotions, and also relate to self-control and environment selection. THE AIM OF THE STUDY The aim of this study was to investigate the association of the rs4680 polymorphism of COMT with personality dimensions and anxiety in patients addicted to stimulants other than cocaine (F15 according to WHO ICD-10 nomenclature) in the case of examined patients amphetamine. METHODS The study was conducted among patients addicted to stimulants other than cocaine (amphetamine). The study group included 247 patients addicted to stimulants (amphetamine) and the control group comprised 280 healthy male volunteers. The real-time PCR method was used to carry out genetic tests; personality dimensions were assessed using the standardized NEO-FFI and state and trait anxiety were assessed with STAI. All analyses were performed using STATISTICA 13. RESULTS The results of the 2 × 3 factorial ANOVA showed a statistically significant effect of the combined factor COMT rs4680 genotype on the group of patients diagnosed with other stimulants dependence/control (F2,252 = 3.11, p = 0.0465, η2 = 0.024). Additionally, we observed that the results of the 2 × 3 factorial ANOVA showed a statistically significant influence of the combined factor COMT rs4680 on the genotype in the group of patients diagnosis with other stimulants dependence/control (F2,252 = 6.16, p = 0.0024, η2 = 0.047). CONCLUSIONS In our research, the polymorphism G/G COMT rs4680 genotype was associated with higher scores of STAI traits and STAI states in the patients dependent on amphetamine. In the control group we observed no such interactions.
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White O, Roeder N, Blum K, Eiden RD, Thanos PK. Prenatal Effects of Nicotine on Obesity Risks: A Narrative Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:9477. [PMID: 35954830 PMCID: PMC9368674 DOI: 10.3390/ijerph19159477] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/25/2022] [Accepted: 07/29/2022] [Indexed: 11/16/2022]
Abstract
Nicotine usage by mothers throughout pregnancy has been observed to relate to numerous deleterious effects in children, especially relating to obesity. Children who have prenatally been exposed to nicotine tend to have lower birth weights, with an elevated risk of becoming overweight throughout development and into their adolescent and adult life. There are numerous theories as to how this occurs: catch-up growth theory, thrifty phenotype theory, neurotransmitter or endocrine imbalances theory, and a more recent examination on the genetic factors relating to obesity risk. In addition to the negative effect on bodyweight and BMI, individuals with obesity may also suffer from numerous comorbidities involving metabolic disease. These may include type 1 and 2 diabetes, high cholesterol levels, and liver disease. Predisposition for obesity with nicotine usage may also be associated with genetic risk alleles for obesity, such as the DRD2 A1 variant. This is important for prenatally nicotine-exposed individuals as an opportunity to provide early prevention and intervention of obesity-related risks.
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Affiliation(s)
- Olivia White
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA; (O.W.); (N.R.)
- Department of Psychology, University at Buffalo, Buffalo, NY 14203, USA
| | - Nicole Roeder
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA; (O.W.); (N.R.)
- Department of Psychology, University at Buffalo, Buffalo, NY 14203, USA
| | - Kenneth Blum
- Division of Addiction Research, Center for Psychiatry, Medicine & Primary Care (Office of Provost), Western University Health Sciences, Pomona, CA 91766, USA;
| | - Rina D. Eiden
- Department of Psychology, Social Science Research Institute, The Pennsylvania State University, University Park, PA 16801, USA;
| | - Panayotis K. Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA; (O.W.); (N.R.)
- Department of Psychology, University at Buffalo, Buffalo, NY 14203, USA
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Andersson BÅ, Nilsson M, Oliva D. Impact of single nucleotide polymorphisms and cigarette smoking on cancer risk and survival of patients with head and neck squamous cell carcinoma. Biomarkers 2022; 27:694-700. [PMID: 35830713 DOI: 10.1080/1354750x.2022.2102210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a disease involving genetic and lifestyle risk factors such as smoking or high-risk papillomavirus (HR-HPV) infections. This study analyzed 92 single nucleotide polymorphisms (SNPs) associated with smoking and HPV on HNSCC cancer risk and survival among HNSCC patients. Eighty-six HNSCC patients (48 non-smoking and 38 smoking) were consecutively included. Differences were detected in the analysis of survival and SNP genotypes located in the CXCR2 and COMT. Five SNPs in genes PRKDC, TGFb, XRCC1, Cyp2A6 and CTLA4 were found to be different when comparing SNP genotypes in all patients and all controls as a risk of HNSCC. When comparing SNP genotypes among smoking patients and smoking controls, six SNPs in the genes PFR1, IL10, CCL4, IL6, Ku70, and PRF1 were detected. When comparing SNP genotypes, nine SNPs in CHRNA3, PRKDC, CHARNA5, IFN-γ, ESR1, XRCC1, Cyp2A6, CTLA4, and COMT were different in non-smoking patients and non-smoking controls. No association was found between SNP distribution or patient survival and the impact of HR-HPV. The SNPs differed between smokers and non-smokers and could indicate a possible interaction between genetics and smoking. This could play an important role in a better understanding of the pathogenesis of HNSCC.
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Affiliation(s)
- Bengt-Åke Andersson
- Department of Natural Science and Biomedicine, School of Welfare, Jönköping University, Jönköping, Sweden
| | - Mats Nilsson
- Department of Health, Medicine and Caring, Linköping University, Linköping, Sweden
| | - Delmy Oliva
- Department of Oncology, Region Jönköping County, Jönköping, Sweden and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Quraishi R, Sharma J, Jain R, Ambekar A. Influence of catechol-O-methyltransferase enzyme gene polymorphism on alcohol and tobacco consumption in North Indian treatment seeking population. Indian J Psychiatry 2021; 63:240-244. [PMID: 34211216 PMCID: PMC8221225 DOI: 10.4103/psychiatry.indianjpsychiatry_465_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 09/17/2020] [Accepted: 05/30/2021] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND The co-occurrence of alcohol and tobacco dependence is frequently witnessed in treatment settings. It is a challenge for clinicians to treat such patients due to their powerful biological association. AIM The study is aimed to assess the relationship of Catechol-O-methyltransferase (COMT) Val158Met polymorphism with substance intake among individuals who are dependent on both alcohol and tobacco. MATERIALS AND METHODS A cross-sectional study involving patients coming to the outpatient department was planned. Brief information on their sociodemographic and substance use profile was recorded. Genotyping of COMT Val158Met was carried out using established polymerase chain reaction-restriction fragment length polymorphism method. The COMT genotyping was classified based on the presence or absence of Met allele using the dominant model. Descriptive statistics, Chi-square test, Mann-Whitney test, and Binary logistic regression analysis were performed to analyze the data. RESULTS The study included 104 alcohol and nicotine co-dependent subjects. More than eighty percent of the participants were educated above secondary level, married, and employed. The allele frequencies of met and Val were found to be 0.23 and 0.77, respectively. Forty percent of the participants reported tobacco-related health problems. The odds of consuming alcohol and nicotine were four times high among Met allele carriers. While the Fagerström test for nicotine dependence and heaviness of smoking index scores were up to four and eight times higher among met allele (odds ratio 4.3 and 8.9, respectively). CONCLUSION Patients carrying Met allele are reported to consume higher amounts of alcohol and tobacco and were likely to score high among measures of nicotine dependence. Thus met allele carriers needs additional attention for a successful treatment outcome.
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Affiliation(s)
- Rizwana Quraishi
- Department of Psychiatry, National Drug Dependence Treatment Center, All India Institute of Medical Sciences, Delhi, India
| | - Jaydeep Sharma
- Department of Psychiatry, National Drug Dependence Treatment Center, All India Institute of Medical Sciences, Delhi, India
| | - Raka Jain
- Department of Psychiatry, National Drug Dependence Treatment Center, All India Institute of Medical Sciences, Delhi, India
| | - Atul Ambekar
- Department of Psychiatry, National Drug Dependence Treatment Center, All India Institute of Medical Sciences, Delhi, India
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Fuertes I, Barata C. Characterization of neurotransmitters and related metabolites in Daphnia magna juveniles deficient in serotonin and exposed to neuroactive chemicals that affect its behavior: A targeted LC-MS/MS method. CHEMOSPHERE 2021; 263:127814. [PMID: 32822934 DOI: 10.1016/j.chemosphere.2020.127814] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 06/11/2023]
Abstract
Neurotransmitters are endogenous metabolites that play a crucial role within an organism, at the chemical synapses. There is a growing interest in their analytical determination for understanding the neurotoxic effect of contaminants. Daphnia magna represents an excellent aquatic model for these environmental studies, due to its similarities with vertebrates in several neurotransmitters and related gene pathways and because of its wide application in ecotoxicological studies. Within this study, an accurate and sensible method of analysis of 17 neurotransmitters and related precursors and metabolites was developed. The method was validated in terms of sensitivity, reproducibility, precision, and accuracy, and also matrix effect was evaluated. As an independent probe of method validation and applicability, the method was applied to two different scenarios. First, it was used for the study of neurotransmitter levels in genetically mutated tryptophan hydrolase D. magna clones, confirming the absence of serotonin and its metabolite 5-HIAA. Additionally, the method was applied for determining the effects of chemical compounds known to affect different neurotransmitter systems and to alter Daphnia behavior. Significant changes were observed in 13 of the analyzed neurotransmitters across treatments, which were related to the neurotransmitter systems described as being affected by these neurochemicals. These two studies, which provide results on the ways in which the neurotransmitter systems in D. magna are affected, have corroborated the applicability of the presented method, of great importance due to the suitability of this organism for environmental neurotoxicity studies.
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Affiliation(s)
- Inmaculada Fuertes
- Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA), Spanish Research Council (IDAEA, CSIC), Jordi Girona 18, 08034, Barcelona, Spain.
| | - Carlos Barata
- Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA), Spanish Research Council (IDAEA, CSIC), Jordi Girona 18, 08034, Barcelona, Spain.
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Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson's disease. Sci Rep 2020; 10:9521. [PMID: 32533012 PMCID: PMC7293305 DOI: 10.1038/s41598-020-65332-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 05/01/2020] [Indexed: 01/26/2023] Open
Abstract
Catechol-O-methyltransferase (COMT) is one of the main enzymes in dopamine metabolism and is reported to be associated with susceptibility to Parkinson’s disease (PD) and pharmacotherapy. However, researchers mostly focus on the most common polymorphism, rs4680. In this case-control study, we investigated the association of SNPs other than rs4680 with the levodopa (L-dopa) response and other clinical features in Chinese PD patients. Eleven single nucleotide polymorphisms (SNPs) in the COMT gene were genotyped, and clinical data were collected. Patients with the TT genotype of rs165728 or rs174699 had larger daily levodopa equivalent doses (LEDs) than the patients with CC and CT genotypes under the dominant model (p = 0.01421 for rs165728 and p = 0.02302 for rs174699). Under the dominant model, the patients with GG at rs4680 G > A had a lower occurrence of dyskinesia than those with AA and AG (p = 0.0196). Patients with CC at rs4633 had a lower occurrence of dyskinesia than those with TT and TC (p = 0.0429) under the dominant model. The frequencies of the rs174675 T and rs933271 C alleles were higher in PD patients than in the controls (p < 0.05). Our primary results showed the possible association of SNPs other than the most common functional rs4680 in COMT with interindividual variance in the L-dopa daily dose and susceptibility to dyskinesia in Chinese patients, although this was an exploratory study based on a small sample size. Larger and more randomized samples are necessary for further investigation.
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Duan L, Li X, Yan J, Chen Y, Luo R, Zhang Q, Feng X, Li X. Association of COMT Gene Polymorphisms with Response to Methadone Maintenance Treatment Among Chinese Opioid-Dependent Patients. Genet Test Mol Biomarkers 2020; 24:364-369. [DOI: 10.1089/gtmb.2019.0275] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Luxi Duan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- Hunan Children's Hospital, Medical Record Statistics and Library Management Office, Changsha, China
| | - Xingyuan Li
- Supervision Office, Tangshan Animal Health Inspection Institute, Tangshan, China
| | - Junxia Yan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yingyi Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Rui Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Qiang Zhang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiangling Feng
- Center for Preventive Medicine Experiment, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xingli Li
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
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Martínez-Laorden E, Navarro-Zaragoza J, Milanés MV, Laorden ML, Almela P. Cardiac Protective Role of Heat Shock Protein 27 in the Stress Induced by Drugs of Abuse. Int J Mol Sci 2020; 21:E3623. [PMID: 32455528 PMCID: PMC7279295 DOI: 10.3390/ijms21103623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/16/2020] [Accepted: 05/19/2020] [Indexed: 11/16/2022] Open
Abstract
Heat shock proteins (HSP) are induced after different stress situations. Some of these proteins, particularly HSP-27, function as markers to indicate cellular stress or damage and protect the heart during addictive processes. Morphine withdrawal induces an enhancement of sympathetic activity in parallel with an increased HSP-27 expression and phosphorylation, indicating a severe situation of stress. HSP-27 can interact with different intracellular signaling pathways. Propranolol and SL-327 were able to antagonize the activation of hypothalamic-pituitary adrenal (HPA) axis and the phosphorylation of HSP-27 observed during morphine withdrawal. Therefore, β-adrenergic receptors and the extracellular signal-regulated kinase (ERK) pathway would be involved in HPA axis activity, and consequently, in HSP-27 activation. Finally, selective blockade of corticotrophin releasing factor (CRF)-1 receptor and the genetic deletion of CRF1 receptors antagonize cardiac adaptive changes. These changes are increased noradrenaline (NA) turnover, HPA axis activation and decreased HSP-27 expression and phosphorylation. This suggests a link between the HPA axis and HSP-27. On the other hand, morphine withdrawal increases µ-calpain expression, which in turn degrades cardiac troponin T (cTnT). This fact, together with a co-localization between cTnT and HSP-27, suggests that this chaperone avoids the degradation of cTnT by µ-calpain, correcting the cardiac contractility abnormalities observed during addictive processes. The aim of our research is to review the possible role of HSP-27 in the cardiac changes observed during morphine withdrawal and to understand the mechanisms implicated in its cardiac protective functions.
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Affiliation(s)
| | - Javier Navarro-Zaragoza
- Department of Pharmacology, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain; (E.M.-L.); (M.V.M.); (M.L.L.); (P.A.)
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Ma Y, Li J, Xu Y, Wang Y, Yao Y, Liu Q, Wang M, Zhao X, Fan R, Chen J, Zhang B, Cai Z, Han H, Yang Z, Yuan W, Zhong Y, Chen X, Ma JZ, Payne TJ, Xu Y, Ning Y, Cui W, Li MD. Identification of 34 genes conferring genetic and pharmacological risk for the comorbidity of schizophrenia and smoking behaviors. Aging (Albany NY) 2020; 12:2169-2225. [PMID: 32012119 PMCID: PMC7041787 DOI: 10.18632/aging.102735] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/02/2020] [Indexed: 12/13/2022]
Abstract
The prevalence of smoking is significantly higher in persons with schizophrenia (SCZ) than in the general population. However, the biological mechanisms of the comorbidity of smoking and SCZ are largely unknown. This study aimed to reveal shared biological pathways for the two diseases by analyzing data from two genome-wide association studies with a total sample size of 153,898. With pathway-based analysis, we first discovered 18 significantly enriched pathways shared by SCZ and smoking, which were classified into five groups: postsynaptic density, cadherin binding, dendritic spine, long-term depression, and axon guidance. Then, by using an integrative analysis of genetic, epigenetic, and expression data, we found not only 34 critical genes (e.g., PRKCZ, ARHGEF3, and CDKN1A) but also various risk-associated SNPs in these genes, which convey susceptibility to the comorbidity of the two disorders. Finally, using both in vivo and in vitro data, we demonstrated that the expression profiles of the 34 genes were significantly altered by multiple psychotropic drugs. Together, this multi-omics study not only reveals target genes for new drugs to treat SCZ but also reveals new insights into the shared genetic vulnerabilities of SCZ and smoking behaviors.
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Affiliation(s)
- Yunlong Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jingjing Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yinghao Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Maiqiu Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyi Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Rongli Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiali Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhen Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenji Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yigang Zhong
- Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangning Chen
- Institute of Personalized Medicine, University of Nevada at Las Vegas, Las Vegas, NV 89154, USA
| | - Jennie Z Ma
- , Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22904, USA
| | - Thomas J Payne
- Department of Otolaryngology and Communicative Sciences, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Yizhou Xu
- Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuping Ning
- The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenyan Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming D Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
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14
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Zhang R, Volkow ND. Brain default-mode network dysfunction in addiction. Neuroimage 2019; 200:313-331. [DOI: 10.1016/j.neuroimage.2019.06.036] [Citation(s) in RCA: 226] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/14/2019] [Accepted: 06/17/2019] [Indexed: 12/21/2022] Open
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15
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Nadalin S, Rebić J, Šendula Jengić V, Peitl V, Karlović D, Buretić-Tomljanović A. Association between PLA2G6 gene polymorphism for calcium-independent phospholipase A2 and nicotine dependence among males with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2019; 148:9-15. [PMID: 31492433 DOI: 10.1016/j.plefa.2019.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/03/2019] [Accepted: 07/02/2019] [Indexed: 01/08/2023]
Abstract
We investigated the relationship between the rs10798059 (BanI) and rs4375 polymorphisms in the phospholipase A2 (PLA2)G4A and PLA2G6 genes and the risk of nicotine dependence in 263 Croatian patients with schizophrenia. We also examined whether interactions between these polymorphisms and smoking contributed to schizophrenia onset and Positive and Negative Syndrome Scale (PANSS) psychopathology. We found no significant differences in the distribution of PLA2G4A genotypes and alleles according to smoking status, and no effect of the PLA2G4A genotype-smoking interaction on disease onset or PANSS. The PLA2G6-TT homozygous genotype was significantly overrepresented in male smokers compared to nonsmokers (34.7% vs. 17.1%, p < 0.05). These patients had ∼2.6-fold higher risk of becoming smokers than males with heterozygous PLA2G6-CT and homozygous PLA2G6-CC genotypes. In addition, male smokers without the PLA2G6-C allele (PLA2G6-TT homozygous) experienced earlier onset than nonsmoking homozygous PLA2G6-TT males. Thus, the PLA2G6 polymorphism affected the risk of nicotine dependence in male patients and the PLA2G6 genotype-smoking interaction was linked to the age of disease onset.
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Affiliation(s)
- Sergej Nadalin
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000, Rijeka, Croatia.
| | - Jelena Rebić
- Psychiatry Clinic, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | | | - Vjekoslav Peitl
- Department of Psychiatry, Sestre Milosrdnice University Hospital Center and Catholic University of Croatia, Zagreb, Croatia
| | - Dalibor Karlović
- Department of Psychiatry, Sestre Milosrdnice University Hospital Center and Catholic University of Croatia, Zagreb, Croatia
| | - Alena Buretić-Tomljanović
- Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000, Rijeka, Croatia
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16
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Zahid M, Mondal B, LeVan TD, Rogan EG. Estrogen Metabolism in African-American Women with and without Breast Cancer: A Pilot Study. Chem Res Toxicol 2018; 32:190-194. [PMID: 30525503 DOI: 10.1021/acs.chemrestox.8b00285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Studies in Caucasian women have shown that the formation of estrogen-DNA adducts is greater in women at high risk for breast cancer or already diagnosed with the disease. To begin investigating whether the role of estrogens in the etiology of breast cancer is similar in African-American (AA) women, a saliva sample and a spot urine sample were collected from 19 AA women with breast cancer and 23 AA women not diagnosed with breast cancer. In the urine samples, 20 estrogen metabolites, conjugates, and DNA adducts were analyzed by using ultraperformance liquid chromatography/tandem mass spectrometry, and then the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and estrogen conjugates was significantly greater in cases compared to controls (92.4 ± 46.4 vs 38.5 ± 18.9, p < 0.0001). From the saliva samples, genomic DNA was purified and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes, catechol- O-methyltransferase (rs4680) and cytochrome P450 1B1 (rs1056836). There was no association between rs4680 and rs1056836 genotypes and adduct ratios or breast cancer status. This pilot study found higher DNA adduct ratios in women with breast cancer, which suggests that estrogen metabolism is out of balance, and the formation of estrogen-DNA adducts may exert a critical role in breast cancer initiation in AA women.
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Affiliation(s)
- Muhammad Zahid
- Department of Environmental, Agricultural, and Occupational Health, College of Public Health , University of Nebraska Medical Center , Omaha , Nebraska 68198-4388 , United States
| | - Bodhisattwa Mondal
- Department of Environmental, Agricultural, and Occupational Health, College of Public Health , University of Nebraska Medical Center , Omaha , Nebraska 68198-4388 , United States
| | - Tricia D LeVan
- Departments of Epidemiology and Internal Medicine , University of Nebraska Medical Center , Omaha , Nebraska 68198-4395 , United States.,VA Nebraska-Western Iowa Health Care System Research Service , Department of Veterans Affairs Medical Center , 4101 Woolworth Avenue , Omaha , Nebraska 68105 , United States
| | - Eleanor G Rogan
- Department of Environmental, Agricultural, and Occupational Health, College of Public Health , University of Nebraska Medical Center , Omaha , Nebraska 68198-4388 , United States
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17
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Womersley JS, Townsend DM, Kalivas PW, Uys JD. Targeting redox regulation to treat substance use disorder using N‐acetylcysteine. Eur J Neurosci 2018; 50:2538-2551. [PMID: 30144182 DOI: 10.1111/ejn.14130] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/28/2018] [Accepted: 07/25/2018] [Indexed: 12/17/2022]
Abstract
Substance use disorder (SUD) is a chronic relapsing disorder characterized by transitioning from acute drug reward to compulsive drug use. Despite the heavy personal and societal burden of SUDs, current treatments are limited and unsatisfactory. For this reason, a deeper understanding of the mechanisms underlying addiction is required. Altered redox status, primarily due to drug-induced increases in dopamine metabolism, is a unifying feature of abused substances. In recent years, knowledge of the effects of oxidative stress in the nervous system has evolved from strictly neurotoxic to include a more nuanced role in redox-sensitive signaling. More specifically, S-glutathionylation, a redox-sensitive post-translational modification, has been suggested to influence the response to drugs of abuse. In this review we will examine the evidence for redox-mediating drugs as therapeutic tools focusing on N-acetylcysteine as a treatment for cocaine addiction. We will conclude by suggesting future research directions that may further advance this field.
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Affiliation(s)
- Jacqueline S Womersley
- Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 409 Drug Discovery Building, 70 President Street, Charleston, SC, 29425, USA
| | - Danyelle M Townsend
- Department of Drug Discover and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Peter W Kalivas
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Joachim D Uys
- Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 409 Drug Discovery Building, 70 President Street, Charleston, SC, 29425, USA
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18
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Analyzing the genes related to nicotine addiction or schizophrenia via a pathway and network based approach. Sci Rep 2018; 8:2894. [PMID: 29440730 PMCID: PMC5811491 DOI: 10.1038/s41598-018-21297-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/31/2018] [Indexed: 01/02/2023] Open
Abstract
The prevalence of tobacco use in people with schizophrenia is much higher than in general population, which indicates a close relationship between nicotine addiction and schizophrenia. However, the molecular mechanism underlying the high comorbidity of tobacco smoking and schizophrenia remains largely unclear. In this study, we conducted a pathway and network analysis on the genes potentially associated with nicotine addiction or schizophrenia to reveal the functional feature of these genes and their interactions. Of the 276 genes associated with nicotine addiction and 331 genes associated with schizophrenia, 52 genes were shared. From these genes, 12 significantly enriched pathways associated with both diseases were identified. These pathways included those related to synapse function and signaling transduction, and drug addiction. Further, we constructed a nicotine addiction-specific and schizophrenia-specific sub-network, identifying 11 novel candidate genes potentially associated with the two diseases. Finally, we built a schematic molecular network for nicotine addiction and schizophrenia based on the results of pathway and network analysis, providing a systematic view to understand the relationship between these two disorders. Our results illustrated that the biological processes underlying the comorbidity of nicotine addiction and schizophrenia was complex, and was likely induced by the dysfunction of multiple molecules and pathways.
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19
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Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways. Naunyn Schmiedebergs Arch Pharmacol 2018; 391:423-434. [PMID: 29383398 DOI: 10.1007/s00210-018-1470-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 01/18/2018] [Indexed: 12/24/2022]
Abstract
Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic-METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c-Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+ neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment.
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Ou WC, Huang YC, Huang CL, Lin MH, Chen YC, Chen YJ, Liu CN, Chen MC, Huang CS, Chen PL. Interaction between cytochrome P450 2A6 and Catechol-O-Methyltransferase genes and their association with smoking risk in young men. Behav Brain Funct 2017; 13:8. [PMID: 28472995 PMCID: PMC5418756 DOI: 10.1186/s12993-017-0127-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 04/26/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Although some effects of gene-gene interactions on nicotine-dopamine metabolism for smoking behavior have been reported, polymorphisms of cytochrome P450 (CYP) 2A6 and catechol-O-methyltransferase (COMT) have not been studied together to determine their effects on smokers. The aim of this study was to investigate the effects of the interaction between the CYP 2A6 and COMT genes on smoking behavior in young Taiwanese men. RESULTS A self-report questionnaire regarding smoking status was administered to 500 young men. Polymorphisms of the CYP 2A6 and COMT genes as well as urinary nicotine and urinary cotinine levels were determined. The odds ratio for starting smoking was significantly lower in subjects carrying a CYP2A6 low activity/variant COMT rs4680 genotype than in those possessing a CYP2A6 wild-type/variant COMT rs4680 genotype (0.44, 95% confidence interval = 0.19-0.98, P = 0.043). Comparisons of Fagerstrom Test for Nicotine Dependence (FTND), Physiological Cigarette Dependence Scale (PCDS), and Cigarette Withdrawal symptoms (CWS-21) among the smokers with different CYP2A6/COMT polymorphisms were not significantly different. The adjusted urinary nicotine concentrations were not significantly different between the two groups carrying different genotypes. The adjusted urinary cotinine level was significantly different between the COMT rs4680 wild-type group and COMT rs4680 variant group [92.46 ng/μL vs. 118.24 ng/μL (median value), P = 0.041] and between the COMT rs4680 wild-type/COMT rs165599 variant group and COMT rs4680 variant/COMT rs165599 variant group (97.10 ng/μL vs. 122.18 ng/μL, P = 0.022). CONCLUSIONS These findings suggest that a single nucleotide polymorphism (rs4680) of the COMT gene and the interaction between the CYP 2A6 and COMT genes affect smoking status in young Taiwanese men.
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Affiliation(s)
- Wei-Chih Ou
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City, 40601, Taiwan
| | - Yi-Chin Huang
- Division of Infectious Diseases, Jen-Ai Hospital, Taichung, Taiwan
| | - Chih-Ling Huang
- Department of Nursing, Chang Jung Christian University, Tainan, Taiwan
| | - Min-Hsuan Lin
- Administration Center for Research and Education, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Chun Chen
- Administration Center for Research and Education, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ju Chen
- Company Limited of Ditech Enterprise, Taipei, Taiwan
| | - Chen-Nu Liu
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City, 40601, Taiwan
| | - Mei-Chih Chen
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City, 40601, Taiwan
| | - Ching-Shan Huang
- Administration Center for Research and Education, Changhua Christian Hospital, Changhua, Taiwan.
| | - Pei-Lain Chen
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City, 40601, Taiwan.
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Nadalin S, Buretić-Tomljanović A, Lavtar P, Starčević Čizmarević N, Hodžić A, Sepčić J, Kapović M, Peterlin B, Ristić S. The lack of association between angiotensin-converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis. Brain Behav 2017; 7:e00600. [PMID: 28127518 PMCID: PMC5256183 DOI: 10.1002/brb3.600] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 09/14/2016] [Accepted: 10/03/2016] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE Blood-borne angiotensin II is generated from angiotensinogen via cleavage by renin and angiotensin-converting enzyme (ACE), an enzymatic cascade known as the renin-angiotensin system (RAS). Several lines of evidence indicate that ACE, beyond its classical role of mediating blood pressure regulation, might contribute to the etiology of substance addictions by influencing dopaminergic signaling. A functional insertion/deletion (I/D) polymorphism of the ACE gene was associated with risk for being a smoker among individuals with depression and with smoking severity in studies comprising patients with depression and healthy controls. Several reports have described significantly increased ACE activity in cerebrospinal fluid and serum among MS patients. Furthermore, in our previous work with MS patients from Croatian and Slovenian populations, we demonstrated that the ACE-I/D polymorphism contributes to an elevated MS risk among male patients. Here we investigated whether the ACE-I/D polymorphism might influence smoking behavior among patients with MS. PATIENTS AND METHODS Genotyping was performed in 521 patients (males/females: 139/382) using polymerase chain reaction. RESULTS We revealed no significant differences in ACE genotype and allele frequencies between smokers and nonsmokers and no significant association between the ACE-I/D polymorphism and either pack-year smoking history or number of cigarettes smoked daily (p > .05, respectively). CONCLUSION The ACE-I/D polymorphism does not contribute either to risk for nicotine dependence or to smoking severity among MS patients. In the context of reports on the ACE-I/D polymorphism and nicotine dependence among healthy controls and patients with depression, we may speculate that the mechanism by which this polymorphism influences nicotine dependence risk differs in MS compared to depression, although not compared to a healthy population. In addition to angiotensin II, other potential ACE substrates, such as substance P and neurotensin, which also influence dopaminergic neurotransmission (and are proposed to be associated with MS), may deserve study in future.
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Affiliation(s)
- Sergej Nadalin
- Department of Biology and Medical Genetics School of Medicine University of Rijeka Rijeka Croatia
| | | | - Polona Lavtar
- Clinical Institute of Medical Genetics University Medical Centre Ljubljana Slovenia
| | | | - Alenka Hodžić
- Clinical Institute of Medical Genetics University Medical Centre Ljubljana Slovenia
| | - Juraj Sepčić
- Postgraduate Studies School of Medicine University of Rijeka Rijeka Croatia
| | - Miljenko Kapović
- Department of Biology and Medical Genetics School of Medicine University of Rijeka Rijeka Croatia
| | - Borut Peterlin
- Clinical Institute of Medical Genetics University Medical Centre Ljubljana Slovenia
| | - Smiljana Ristić
- Department of Biology and Medical Genetics School of Medicine University of Rijeka Rijeka Croatia
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Wachman EM, Hayes MJ, Sherva R, Brown MS, Shrestha H, Logan BA, Heller NA, Nielsen DA, Farrer LA. Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity. Am J Addict 2017; 26:42-49. [PMID: 27983768 PMCID: PMC5206487 DOI: 10.1111/ajad.12483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/28/2016] [Accepted: 12/04/2016] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND AND OBJECTIVES There is significant variability in severity of neonatal abstinence syndrome (NAS) due to in utero opioid exposure. Our previous study identified single nucleotide polymorphisms (SNPs) in the prepronociceptin (PNOC) and catechol-O-methyltransferase (COMT) genes that were associated with differences in NAS outcomes. This study looks at the same SNPs in PNOC and COMT in an independent cohort in an attempt to replicate previous findings. METHODS For the replication cohort, full-term opioid-exposed newborns and their mothers (n = 113 pairs) were studied. A DNA sample was obtained and genotyped for five SNPs in the PNOC and COMT genes. The association of each SNP with NAS outcomes (length of hospitalization, need for pharmacologic treatment, and total opioid days) was evaluated, with an experiment-wise significance level set at α < .003 and point-wise level of α < .05. SNP associations in a combined cohort of n = 199 pairs (replication cohort plus 86 pairs previously reported), were also examined. RESULTS In the replication cohort, mothers with the COMT rs4680 G allele had infants with a reduced risk for treatment with two medications for NAS (adjusted OR = .5, p = .04), meeting point-wise significance. In the combined cohort, infants with the PNOC rs4732636 A allele had a reduced need for medication treatment (adjusted OR 2.0, p = .04); mothers with the PNOC rs351776 A allele had infants who were treated more often with two medications (adjusted OR 2.3, p = .004) with longer hospitalization by 3.3 days (p = .01). Mothers with the COMT rs740603 A allele had infants who were less often treated with any medication (adjusted OR .5, p = .02). Though all SNP associations all met point wise and clinical significance, they did not meet the experiment-wise significance threshold. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE We found differences in NAS outcomes depending on PNOC and COMT SNP genotype. This has important implications for identifying infants at risk for severe NAS who could benefit from tailored treatment regimens. Further testing in a larger sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants with NAS. (Am J Addict 2017;26:42-49).
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Affiliation(s)
- Elisha M Wachman
- Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts
| | - Marie J Hayes
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine
| | - Richard Sherva
- Department of Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts
| | - Mark S Brown
- Department of Pediatrics, Eastern Maine Medical Center, Bangor, Maine
| | - Hira Shrestha
- Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts
| | - Beth A Logan
- Department of Transplant Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nicole A Heller
- Department of Psychology, Siena College, Loudonville, New York
| | - David A Nielsen
- Department of Psychiatry, Baylor College of Medicine, Houston, Texas
| | - Lindsay A Farrer
- Department of Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts
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Nadalin S, Ristić S, Rebić J, Šendula Jengić V, Kapović M, Buretić-Tomljanović A. The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and nicotine dependence in schizophrenia patients. J Neural Transm (Vienna) 2016; 124:511-518. [DOI: 10.1007/s00702-016-1670-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Accepted: 12/18/2016] [Indexed: 11/29/2022]
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Khalil H, Sereika SM, Dai F, Alexander S, Conley Y, Gruen G, Meng L, Siska P, Tarkin I, Henker R. OPRM1 and COMT Gene-Gene Interaction Is Associated With Postoperative Pain and Opioid Consumption After Orthopedic Trauma. Biol Res Nurs 2016; 19:170-179. [PMID: 27903758 DOI: 10.1177/1099800416680474] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND mu-opioid receptor ( OPRM1) and catechol-O-methyltransferase ( COMT) contribute to the neurotransmission pathway of pain. COMT affects mu receptor expression and density in the brain. The aim of this study was to explore the OPRM1 and COMT interaction effects on postoperative pain and opioid consumption. METHODS This cross-sectional exploratory study used genotype and clinical data from 153 postoperative patients. Using multiple regression analyses, four single-nucleotide polymorphisms of COMT (rs6269, rs4633, rs4818, and rs4680), their haplotypes, and diplotypes were considered for their interactions with A118G of OPRM1 regarding postoperative pain and opioid consumption. RESULTS For opioid consumption, significant interactions were found between OPRM1 A118G and COMT rs4680 ( p = .037) and between OPRM1 and COMT rs4633 ( p = .037). Patients having Met158Met of COMT rs4680 and AG/GG of OPRM1 or TT of COMT rs4633 and AG/GG of OPRM1 consumed the largest amount of opioid compared to those having other combinations. For postoperative pain, a significant interaction was found between OPRM1 and the low pain sensitivity (LPS; GCGG) haplotype of COMT ( p = .017). For patients with no copies of the LPS haplotype, AA of OPRM1 A118G was significantly associated with higher pain scores compared to the variant AG/GG. However, the opposite direction was observed for patients with at least one copy of the LPS haplotype. CONCLUSIONS The interaction of OPRM1 with COMT may contribute to variability in postoperative pain and opioid consumption. Additional larger studies are needed to confirm findings.
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Affiliation(s)
- Heba Khalil
- 1 School of Nursing, Applied Science Private University, Amman, Jordan
| | - Susan M Sereika
- 2 School of Nursing, University of Pittsburgh, Pittsburgh PA, USA
| | - Feng Dai
- 3 Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA
| | - Sheila Alexander
- 2 School of Nursing, University of Pittsburgh, Pittsburgh PA, USA
| | - Yvette Conley
- 2 School of Nursing, University of Pittsburgh, Pittsburgh PA, USA
| | - Gary Gruen
- 4 School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Li Meng
- 4 School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peter Siska
- 4 School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ivan Tarkin
- 4 School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Richard Henker
- 2 School of Nursing, University of Pittsburgh, Pittsburgh PA, USA
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Zhang Y, Feng S, Nie K, Zhao X, Gan R, Wang L, Zhao J, Tang H, Gao L, Zhu R, Wang L, Zhang Y. Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinson's disease. J Neurol Sci 2016; 369:347-353. [DOI: 10.1016/j.jns.2016.08.063] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 08/23/2016] [Accepted: 08/30/2016] [Indexed: 10/21/2022]
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Nadalin S, Buretić-Tomljanović A, Rebić J, Pleša I, Šendula Jengić V. An association between the PPARα-L162V polymorphism and nicotine dependency among patients with schizophrenia. Compr Psychiatry 2016; 70:118-24. [PMID: 27624431 DOI: 10.1016/j.comppsych.2016.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/25/2016] [Accepted: 07/06/2016] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Patients with schizophrenia are more likely to be smokers than the general population, which makes them an interesting group with which to study the etiology of nicotine dependency. We studied the prevalence of a gene variant of peroxisome proliferator-activated receptor alpha (PPARα) in schizophrenia, together with nicotine dependency, to investigate whether the PPARα-L162V polymorphism (rs1800206) influences nicotine dependency in schizophrenia. Given evidence suggesting that smoking influences the severity of schizophrenia, together with our recent data linking the PPARα-L162V polymorphism to clinical manifestations of schizophrenia (in the Croatian population), we hypothesized that interactions between the two (smoking and the PPARα-L162V polymorphism) might contribute to disease onset and scores for the Positive and Negative Syndrome Scale. To the best of our knowledge, this is the first study to investigate the possible associations between the PPARα gene and nicotine dependency. PATIENTS AND METHODS Genotyping was performed for 267 chronically ill schizophrenia patients (males/females: 140/127) by polymerase chain reaction. RESULTS A significant excess of PPARα-L162V genotypes and PPARα-162V alleles were detected among female smokers in comparison to female nonsmokers (18.2% vs. 2.0%, and 9.1% vs. 1.0%, p<0.01, respectively). We also revealed a significant PPARα genotype-smoking interaction that predicted positive symptom severity among male patients (F=4.43, p<0.05). These data indicated that the PPARα-L162V heterozygous genotype, depending on smoking status, might be of relevance as either protective, or a risk factor, for the severity of positive symptoms. No interaction between the PPARα-L162V polymorphism and smoking for the time of onset of schizophrenia was detected (p>0.05, respectively). CONCLUSION We demonstrated two significant yet weak effects. The first showed an effect of the PPARα-L162V polymorphism on the risk of nicotine dependency. The second linked the PPARα genotype-smoking interaction to positive symptoms severity among schizophrenia patients; both effects manifested in a gender-specific fashion.
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Affiliation(s)
- Sergej Nadalin
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
| | - Alena Buretić-Tomljanović
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
| | - Jelena Rebić
- Psychiatry Clinic, Clinical Hospital Center Rijeka, Cambierieva 15, 51000 Rijeka, Croatia
| | - Ivana Pleša
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
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Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions. Mol Psychiatry 2016; 21:992-1008. [PMID: 27166759 PMCID: PMC4956568 DOI: 10.1038/mp.2016.67] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 03/05/2016] [Accepted: 03/09/2016] [Indexed: 12/18/2022]
Abstract
Experimental approaches to genetic studies of complex traits evolve with technological advances. How do discoveries using different approaches advance our knowledge of the genetic architecture underlying complex diseases/traits? Do most of the findings of newer techniques, such as genome-wide association study (GWAS), provide more information than older ones, for example, genome-wide linkage study? In this review, we address these issues by developing a nicotine dependence (ND) genetic susceptibility map based on the results obtained by the approaches commonly used in recent years, namely, genome-wide linkage, candidate gene association, GWAS and targeted sequencing. Converging and diverging results from these empirical approaches have elucidated a preliminary genetic architecture of this intractable psychiatric disorder and yielded new hypotheses on ND etiology. The insights we obtained by putting together results from diverse approaches can be applied to other complex diseases/traits. In sum, developing a genetic susceptibility map and keeping it updated are effective ways to keep track of what we know about a disease/trait and what the next steps may be with new approaches.
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Abstract
The past decade has witnessed a number of societal and political changes that have raised critical questions about the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and behavioral effects of cannabinoids that have been observed within one's lifetime and even into the subsequent generation. Here, we provide an overview of the current published scientific literature that has examined epigenetic effects of cannabinoids. Though mechanistic insights about the epigenome remain sparse, accumulating data in humans and animal models have begun to reveal aberrant epigenetic modifications in brain and the periphery linked to cannabis exposure. Expansion of such knowledge and causal molecular relationships could help provide novel targets for future therapeutic interventions.
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Baker TE, Stockwell T, Barnes G, Haesevoets R, Holroyd CB. Reward Sensitivity of ACC as an Intermediate Phenotype between DRD4-521T and Substance Misuse. J Cogn Neurosci 2016; 28:460-71. [DOI: 10.1162/jocn_a_00905] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Abstract
The development and expression of the midbrain dopamine system is determined in part by genetic factors that vary across individuals such that dopamine-related genes are partly responsible for addiction vulnerability. However, a complete account of how dopamine-related genes predispose individuals to drug addiction remains to be developed. Adopting an intermediate phenotype approach, we investigated whether reward-related electrophysiological activity of ACC—a cortical region said to utilize dopamine reward signals to learn the value of extended, context-specific sequences of goal-directed behaviors—mediates the influence of multiple dopamine-related functional polymorphisms over substance use. We used structural equation modeling to examine whether two related electrophysiological phenomena associated with the control and reinforcement learning functions of ACC—theta power and the reward positivity—mediated the relationship between the degree of substance misuse and genetic polymorphisms that regulate dopamine processing in frontal cortex. Substance use data were collected from 812 undergraduate students. One hundred ninety-six returned on a subsequent day to participate in an electrophysiological experiment and to provide saliva samples for DNA analysis. We found that these electrophysiological signals mediated a relationship between the DRD4-521T dopamine receptor genotype and substance misuse. Our results provide a theoretical framework that bridges the gap between genes and behavior in drug addiction and illustrate how future interventions might be individually tailored for specific genetic and neurocognitive profiles.
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Wachman EM, Hayes MJ, Sherva R, Brown MS, Davis JM, Farrer LA, Nielsen DA. Variations in opioid receptor genes in neonatal abstinence syndrome. Drug Alcohol Depend 2015; 155:253-9. [PMID: 26233486 PMCID: PMC4581974 DOI: 10.1016/j.drugalcdep.2015.07.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 07/01/2015] [Accepted: 07/01/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. METHODS Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. RESULTS SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. CONCLUSIONS These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.
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Affiliation(s)
- Elisha M Wachman
- Pediatrics, Boston Medical Center, 771 Albany Street, Dowling 4N 4109, Boston, MA 02118, United States.
| | - Marie J Hayes
- Graduate School of Biomedical Science & Engineering, University of Maine, Orono, ME 04469, United States.
| | - Richard Sherva
- Biomedical Genetics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, United States.
| | - Mark S Brown
- Pediatrics, Eastern Maine Medical Center, 489 State St, Bangor, ME 04401, United States.
| | - Jonathan M Davis
- Pediatrics, The Floating Hospital for Children at Tufts Medical Center, 755 Washington Street, Boston, MA 02116, United States.
| | - Lindsay A Farrer
- Biomedical Genetics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, United States.
| | - David A Nielsen
- Psychology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States.
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Bidwell LC, McGeary JE, Gray JC, Palmer RHC, Knopik VS, MacKillop J. An initial investigation of associations between dopamine-linked genetic variation and smoking motives in African Americans. Pharmacol Biochem Behav 2015; 138:104-10. [PMID: 26410615 DOI: 10.1016/j.pbb.2015.09.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 08/05/2015] [Accepted: 09/24/2015] [Indexed: 11/25/2022]
Abstract
Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences that may vary across ethnicities. The use of intermediate phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work in European Americans has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives represent core features of nicotine dependence and are promising intermediate phenotypes for understanding genetic pathways to ND. However, no studies have examined PDM as an intermediate phenotype in African American smokers, an ethnic population that displays unique patterns of smoking and genetic variation. In the current study, 268 African American daily smokers completed a phenotypic assessment and provided a sample of DNA. Associations among haplotypes in the NCAM1-TTC12-ANKK1-DRD2 gene cluster, a dopamine-related gene region associated with ND, PDM intermediate phenotypes, and ND were examined. Dopamine-related genetic variation in the DBH and COMT genes was also considered on an exploratory basis. Mediational analysis was used to test the indirect pathway from genetic variation to smoking motives to nicotine dependence. NCAM1-TTC12-ANKK1-DRD2 region variation was significantly associated with the Automaticity subscale and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and ND. DBH was also significantly associated with Automaticity, Craving, and Tolerance; Automaticity and Tolerance also served as mediators of the DBH-ND relationship. These results suggest that PDM, Automaticity in particular, may be a viable intermediate phenotype for understanding dopamine-related genetic influences on ND in African American smokers. Findings support a model in which putatively dopaminergic variants exert influence on ND through an effect on patterns of automatic routinized smoking.
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Affiliation(s)
- L C Bidwell
- Institute of Cognitive Science, University of Colorado at Boulder, Boulder, CO 80304, United States; Division of Behavioral Genetics, Rhode Island Hospital, 1 Hoppin St., Providence, RI 02903, United States; Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI 02903, United States.
| | - J E McGeary
- Providence Veterans Affairs Medical Center, 830 Chalkstone Avenue, Building 35, Providence, RI 02908, United States; Division of Behavioral Genetics, Rhode Island Hospital, 1 Hoppin St., Providence, RI 02903, United States; Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI 02903, United States
| | - J C Gray
- Department of Psychology, 100 Hooper St., University of Georgia, Athens, GA 30602, United States
| | - R H C Palmer
- Division of Behavioral Genetics, Rhode Island Hospital, 1 Hoppin St., Providence, RI 02903, United States; Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI 02903, United States
| | - V S Knopik
- Division of Behavioral Genetics, Rhode Island Hospital, 1 Hoppin St., Providence, RI 02903, United States; Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI 02903, United States
| | - J MacKillop
- Peter Boris Centre for Addictions Research, McMaster University/St. Joseph's Healthcare Hamilton, 100 West 5th At., Hamilton, ON L8N 3K7, Canada
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Yu W, Tu D, Hong F, Wang J, Liu X, Cai Y, Xu R, Zhao G, Wang F, Pan H, Wu S, Feng T, Wang B. Analysis of the Association between Catechol‐O‐Methyltransferase Val158Met and Male Sexual Orientation. J Sex Med 2015; 12:1920-6. [DOI: 10.1111/jsm.12978] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Bowers H, Smith D, de la Salle S, Choueiry J, Impey D, Philippe T, Dort H, Millar A, Daigle M, Albert PR, Beaudoin A, Knott V. COMT polymorphism modulates the resting-state EEG alpha oscillatory response to acute nicotine in male non-smokers. GENES, BRAIN, AND BEHAVIOR 2015; 14:466-76. [PMID: 26096691 PMCID: PMC4514526 DOI: 10.1111/gbb.12226] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 06/15/2015] [Accepted: 06/15/2015] [Indexed: 11/28/2022]
Abstract
Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists, and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting-state electroencephalographic (EEG) oscillations. In a sample of 62 healthy non-smoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo-controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in frontocentral regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT.
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Affiliation(s)
- H. Bowers
- Department of Psychology, University of Guelph, Guelph, ON, Canada
| | - D. Smith
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - S. de la Salle
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
| | - J. Choueiry
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - D. Impey
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
| | - T. Philippe
- University of Ottawa Institute of Mental Health Research, Royal Ottawa Mental Health Care Centre, Ottawa, ON, Canada
| | - H. Dort
- University of Ottawa Institute of Mental Health Research, Royal Ottawa Mental Health Care Centre, Ottawa, ON, Canada
| | - A. Millar
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - M. Daigle
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - P. R. Albert
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - A. Beaudoin
- University of Ottawa Institute of Mental Health Research, Royal Ottawa Mental Health Care Centre, Ottawa, ON, Canada
| | - V. Knott
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
- University of Ottawa Institute of Mental Health Research, Royal Ottawa Mental Health Care Centre, Ottawa, ON, Canada
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Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction. BMC SYSTEMS BIOLOGY 2015; 9:25. [PMID: 26044620 PMCID: PMC4456775 DOI: 10.1186/s12918-015-0167-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 05/12/2015] [Indexed: 01/09/2023]
Abstract
Background Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Results Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Conlusions Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics. Electronic supplementary material The online version of this article (doi:10.1186/s12918-015-0167-x) contains supplementary material, which is available to authorized users.
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Tang X, Zhan S, Yang L, Cui W, Ma JZ, Payne TJ, Li MD. Ethnic-specific genetic association of variants in the corticotropin-releasing hormone receptor 1 gene with nicotine dependence. BIOMED RESEARCH INTERNATIONAL 2015; 2015:263864. [PMID: 25802844 PMCID: PMC4352749 DOI: 10.1155/2015/263864] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 01/05/2015] [Indexed: 11/21/2022]
Abstract
Twin and family studies indicate that smoking addiction is highly influenced by genetic factors. Variants in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been associated with alcoholism and depression. In this study, we tested five single nucleotide polymorphisms (SNPs) in CRHR1 for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström test for ND (FTND) in 2,037 subjects from 602 families of either European American (EA) or African American (AA) ancestry. Association analysis of the five SNPs revealed a significant association of rs171440 with SQ in the AA sample and with SQ and FTND in the pooled AA and EA samples. Haplotype-based association analysis indicated significant association of haplotypes C-C (56.9%) and T-C (38.9%), formed by SNPs rs171440 and rs1396862, with SQ in the AA sample, C-C-G (47.6%) with SQ, and T-C-G (42.3%), formed by SNPs rs171440, rs1396862, and rs878886, with SQ and FTND in the pooled AA and EA samples. However, none of these associations remained significant after correction for multiple testing. Together, our results provide suggestive evidence for the involvement of CRHR1 in ND, which warrants further investigation using larger independent samples.
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Affiliation(s)
- Xiujun Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Shumin Zhan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Liping Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Wenyan Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Jennie Z. Ma
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
| | - Thomas J. Payne
- Department of Otolaryngology and Communicative Sciences, ACT Center for Tobacco Treatment, Education and Research, University of Mississippi Medical Center, Jackson, MS 39213, USA
| | - Ming D. Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22904, USA
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Wu Y, Fan H, Wang Y, Zhang L, Gao X, Chen Y, Li J, Ren H, Gao H. Genome-wide association studies using haplotypes and individual SNPs in Simmental cattle. PLoS One 2014; 9:e109330. [PMID: 25330174 PMCID: PMC4203724 DOI: 10.1371/journal.pone.0109330] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 09/10/2014] [Indexed: 01/05/2023] Open
Abstract
Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components.
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Affiliation(s)
- Yang Wu
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - Huizhong Fan
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - Yanhui Wang
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - Lupei Zhang
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - Xue Gao
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - Yan Chen
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - Junya Li
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
| | - HongYan Ren
- Department of life sciences, National Natural Science Foundation of China, Beijing, China
- * E-mail: (HG); (HR)
| | - Huijiang Gao
- Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing, China
- * E-mail: (HG); (HR)
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Martínez-Laorden E, García-Carmona JA, Baroja-Mazo A, Romecín P, Atucha NM, Milanés MV, Laorden ML. Corticotropin-releasing factor (CRF) receptor-1 is involved in cardiac noradrenergic activity observed during naloxone-precipitated morphine withdrawal. Br J Pharmacol 2014; 171:688-700. [PMID: 24490859 DOI: 10.1111/bph.12511] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 09/27/2013] [Accepted: 10/03/2013] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND AND PURPOSE The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [noradrenergic activity, induction of the hypothalamic-pituitary-adrenocortical (HPA) axis and activation of heat shock proteins (Hsps)]. Corticotropin-releasing factor (CRF) pathways are important mediators in the negative symptoms of opioid withdrawal. We performed a series of experiments to characterize the role of the CRF₁ receptor in the response of stress systems to morphine withdrawal and its effect in the heart using genetically engineered mice lacking functional CRF₁ receptors. EXPERIMENTAL APPROACH Wild-type and CRF₁ receptor-knockout mice were treated with increasing doses of morphine. Precipitated withdrawal was induced by naloxone. Plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, the expression of myocardial Hsp27, Hsp27 phosphorylated at Ser⁸², membrane (MB)- COMT, soluble (S)-COMT protein and NA turnover were evaluated by RIA, immunoblotting and HPLC. KEY RESULTS During morphine withdrawal we observed an enhancement of NA turnover in parallel with an increase in mean arterial blood pressure (MAP) and heart rate (HR) in wild-type mice. In addition, naloxone-precipitated morphine withdrawal induced an activation of HPA axis and Hsp27. The principal finding of the present study was that plasma ACTH and corticosterone levels, MB-COMT, S-COMT, NA turnover, and Hsp27 expression and activation observed during morphine withdrawal were significantly inhibited in the CRF₁ receptor-knockout mice. CONCLUSION AND IMPLICATIONS Our results demonstrate that CRF/CRF₁ receptor activation may contribute to stress-induced cardiovascular dysfunction after naloxone-precipitated morphine withdrawal and suggest that CRF/CRF₁ receptor pathways could contribute to cardiovascular disease associated with opioid addiction.
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Katz AC, Sarapas C, Bishop JR, Patel SR, Shankman SA. The mediating effect of prefrontal asymmetry on the relationship between the COMT Val(158)Met SNP and trait consummatory positive affect. Cogn Emot 2014; 29:867-81. [PMID: 25195915 DOI: 10.1080/02699931.2014.951030] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
The Val(158)Met rs4680 polymorphism in the COMT gene regulates dopamine catabolism in the prefrontal cortex (PFC). Dopamine's involvement in reward experience suggests those with the methionine (Met) variant may exhibit trait-level sensitivity to reward due to more post-synaptic dopamine in the PFC. A physiological mediator of this association may be greater relative left asymmetry in the PFC, a putative biomarker for trait positive emotionality. Electroencephalograms of 120 participants were measured during a task that assesses two aspects of reward processing: pre-reward anticipation and post-reward consummatory affect. Participants provided genetics samples and completed the Temporal Experience of Pleasure Scale (TEPS), which assesses trait-level anticipatory and consummatory positive affect. Met carriers had higher TEPS-Consummatory scores. This effect was mediated by greater relative left activation in the post-reward phase of the task. No effects were observed for the pre-reward phase. Results suggest that frontal asymmetry is an endophenotype between COMT genotype and trait reward responsivity.
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Affiliation(s)
- Andrea C Katz
- a Department of Psychology , University of Illinois at Chicago , Chicago , IL , USA
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van der Knaap LJ, Schaefer JM, Franken IHA, Verhulst FC, van Oort FVA, Riese H. Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study. GENES BRAIN AND BEHAVIOR 2014; 13:618-25. [PMID: 24902721 DOI: 10.1111/gbb.12147] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 05/16/2014] [Accepted: 06/02/2014] [Indexed: 12/18/2022]
Abstract
Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158) Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158) Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158) Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.
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Affiliation(s)
- L J van der Knaap
- Department of Child and Adolescent Psychiatry & Psychology, Erasmus Medical Center, The Netherlands
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Catecholaminergic gene variants: contribution in ADHD and associated comorbid attributes in the eastern Indian probands. BIOMED RESEARCH INTERNATIONAL 2013; 2013:918410. [PMID: 24163823 PMCID: PMC3791561 DOI: 10.1155/2013/918410] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 08/07/2013] [Accepted: 08/12/2013] [Indexed: 12/25/2022]
Abstract
Contribution of genes in attention deficit hyperactivity disorder (ADHD) has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N = 170), their parents (N = 310), and ethnically matched controls (n = 180) was used for genotyping followed by population- and family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission (P < 0.05). rs3837091 “AGAG,” rs3735273 “A,” rs1799732 “C,” rs740603 “G,” rs165599 “G” and single repeat alleles of rs4646984/rs4646983 showed positive correlation with co-morbid characteristics (P < 0.05). Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P < 0.001), while family-based data showed interaction between DDC and DRD2 (P = 0.04). This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD.
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Han DH, Lee YS, Yang KC, Kim EY, Lyoo IK, Renshaw PF. Dopamine genes and reward dependence in adolescents with excessive internet video game play. J Addict Med 2013; 1:133-8. [PMID: 21768948 DOI: 10.1097/adm.0b013e31811f465f] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Excessive internet video game play (EIGP) has emerged as a leading cause of behavioral and developmental problems in adolescents. Recent research has implicated the role of striatal dopaminergic system in the behavioral maladaptations associated with EIGP. This study investigates the reward-dependence characteristics in EIGP adolescents as it potentially relates to genetic polymorphisms of the dopaminergic system and temperament. Seventy-nine male EIGP adolescents and 75 age- and gender-matched healthy comparison adolescents were recruited. Associations were tested with respect to the reward-dependence (RD) scale in Cloninger's Temperament and Character Inventory and the frequencies of 3 dopamine polymorphisms: Taq1A1 allele of the dopamine D2 receptor (DRD2 Taq1A1) and Val158Met in the Catecholamine-O-Methyltransferase (COMT) genes. The Taq1A1 and low activity (COMT) alleles were significantly more prevalent in the EIGP group relative to the comparison group. The present EIGP group had significantly higher RD scores than controls. Within the EIGP group, the presence of the Taq1A1 allele correlated with higher RD scores. Our findings suggest that EIGP subjects have higher reward dependency and an increased prevalence of the DRD2 Taq1A1 and COMT alleles. In particular, the DRD2 Taq1A1 allele seems to be associated with reward dependence in EIGP adolescents.
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Affiliation(s)
- Doug Hyun Han
- From McLean Hospital Brain Imaging Center and Department of Psychiatry (DHH, KCY, IKL, PFR), Harvard Medical School, Belmont, MA; the Department of Psychiatry (YSL, EYK), Chung-Ang University Medical School, Seoul, South Korea; and the Department of Psychiatry (IKL), Seoul National University College of Medicine, Seoul, South Korea
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Ashare RL, Falcone M, Lerman C. Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. Neuropharmacology 2013; 76 Pt B:581-91. [PMID: 23639437 DOI: 10.1016/j.neuropharm.2013.04.034] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 04/04/2013] [Accepted: 04/16/2013] [Indexed: 11/25/2022]
Abstract
Nicotine withdrawal is associated with deficits in neurocognitive function including sustained attention, working memory, and response inhibition. Several convergent lines of evidence suggest that these deficits may represent a core dependence phenotype and a target for treatment development efforts. A better understanding of the mechanisms underlying withdrawal-related cognitive deficits may lead to improve nicotine dependence treatment. We begin with an overview of the neurocognitive effects of withdrawal in rodent and human models, followed by discussion of the neurobehavioral mechanisms that are thought to underlie these effects. We then review individual differences in withdrawal-related neurocognitive effects including genetics, gender, and psychiatric comorbidity. We conclude with a discussion of the implications of this research for developing improved therapies, both pharmacotherapy and behavioral treatments, that target cognitive symptoms of nicotine withdrawal. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
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Affiliation(s)
- Rebecca L Ashare
- Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, PA 19104, USA.
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Mutschler J, Abbruzzese E, von der Goltz C, Dinter C, Mobascher A, Thiele H, Diaz-Lacava A, Dahmen N, Gallinat J, Majic T, Petrovsky N, Thuerauf N, Kornhuber J, Gründer G, Rademacher L, Brinkmeyer J, Wienker T, Wagner M, Winterer G, Kiefer F. Lack of association of a functional catechol-O-methyltransferase gene polymorphism with risk of tobacco smoking: results from a multicenter case-control study. Nicotine Tob Res 2013; 15:1322-7. [PMID: 23288874 DOI: 10.1093/ntr/nts334] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior. METHODS In a population-based case-control multicenter study designed for tobacco addiction research, a total of 551 current smokers of European ancestry and 548 age-matched healthy volunteers (never-smokers) were genotyped for SNP rs4680 and extensively characterized concerning their smoking behavior. RESULTS We found no association between smoking status and SNP rs4680 genotype nor did we find a significant association to the degree of tobacco dependence. CONCLUSIONS Although prefrontal cortical and ventral striatal activity are highly relevant for addictive behavior, and under partial control of COMT rs4680 genotype, no association between COMT and smoking behavior was observed. Other genetic variants may account for the high heritability of behavioral smoking phenotypes.
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Affiliation(s)
- Jochen Mutschler
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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Abstract
Nicotine addiction (NA) is a common and devastating disease, such that the annual number of deaths (world-wide) from tobacco-related diseases will double from 5 million in the year 2000 to 10 million in 2020. Nicotine is the only substance in tobacco which animals and humans will self-administer. NA, as a lifetime diagnosis, has been assessed in various approaches, including the concept of cigarettes per day (CPD). Other assessments of NA are somewhat more comprehensive, such as the Fagerstrom Test for Nicotine Dependence or the American Psychiatric Association's Diagnostic and Statistical Manual (fourth edition) diagnosis of nicotine dependence. These different measures have moderate agreement with one another. Twin, family and adoption studies have shown that these different assessments of NA have substantial heritability (that fraction of risk attributable to genetic factors). The heritability of NA has been estimated at 50-75%, depending on the definition and the population under study. DNA-based studies of NA have been somewhat successful in identifying a common haplotype, which increases risk for NA among European-origin populations. This haplotype explains a small amount of variance, accounting for ∼1 CPD, and it includes the α5 and the α3 nicotinic receptor subunit genes (CHRNA5 and CHRNA3). The review will focus on this implicated region. In this risk region, there is a common (among European-origin people) mis-sense single-nucleotide polymorphism in the CHRNA5 gene (D398N), which changes a conserved amino acid from aspartic acid to asparagine. The risk allele (398N) confers decreased calcium permeability and more extensive desensitization, according to in vitro cellular studies, raising the possibility that a positive allosteric modulator of the (α4β2)(2)α5 type of nicotinic receptor might have therapeutic potential in NA. There are other genetic influences on NA in this region, apart from the mis-sense variant, and additional biological experiments must be done to understand them.
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Affiliation(s)
- W H Berrettini
- Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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Witte AV, Flöel A. Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2012; 88:418-28. [DOI: 10.1016/j.brainresbull.2011.11.012] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 11/03/2011] [Accepted: 11/15/2011] [Indexed: 12/24/2022]
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Suriyaprom K, Tungtrongchitr R, Harnroongroj T. Impact of COMT Val 108/158 Met and DRD2 Taq1B Gene Polymorphisms on Vulnerability to Cigarette Smoking of Thai Males. J Mol Neurosci 2012; 49:544-9. [DOI: 10.1007/s12031-012-9844-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Accepted: 06/14/2012] [Indexed: 10/28/2022]
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dos Santos VA, Chatkin JM, Bau CHD, Paixão-Côrtes VR, Sun Y, Zamel N, Siminovitch K. Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study. PLoS One 2012; 7:e38666. [PMID: 22719919 PMCID: PMC3377718 DOI: 10.1371/journal.pone.0038666] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 05/14/2012] [Indexed: 11/29/2022] Open
Abstract
Smoking behavior is a multifactorial phenotype with significant heritability. Identifying the specific loci that influence smoking behavior could provide important etiological insights and facilitate the development of treatments to further reduce smoking related mortality. Although several studies pointed to different candidate genes for smoking, there is still a need for replication especially in samples from different countries. In the present study, we investigated whether 21 positive signals for smoking behavior from these studies are replicated in a sample of 531 blood donors from the Brazilian population. The polymorphisms were chosen based on their representativeness of different candidate biologic systems, strength of previous evidence, location and allele frequencies. By genotyping with the Sequenom MassARRAY iPLEX platform and subsequent statistical analysis using Plink software, we show that two of the SNPs studied, in the SLC1A2 (rs1083658) and ACTN1 (rs2268983) genes, were associated with smoking behavior in our study population. These genes are involved in crucial aspects of nicotine dependence, glutamate system and synaptic plasticity, and as such, are biologically plausible candidates that merit further molecular analyses so as to clarify their potential role in smoking behavior.
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Affiliation(s)
| | - Jose Miguel Chatkin
- School of Medicine, Pontificia Universidade Católica Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Claiton Henrique Dotto Bau
- Departament of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Ye Sun
- Department of Medicine, University of Toronto, Toronto, Canada
- Departments of Immunology and Molecular Genetics, University of Toronto and Samuel Lunenfeld and Toronto General Hospital Research Institutes, Toronto, Ontario, Canada
| | - Noe Zamel
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Katherine Siminovitch
- Department of Medicine, University of Toronto, Toronto, Canada
- Departments of Immunology and Molecular Genetics, University of Toronto and Samuel Lunenfeld and Toronto General Hospital Research Institutes, Toronto, Ontario, Canada
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Association of functional COMT Val108/Met polymorphism with smoking cessation in a nicotine replacement therapy. J Neural Transm (Vienna) 2012; 119:1491-8. [PMID: 22695756 DOI: 10.1007/s00702-012-0841-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 05/27/2012] [Indexed: 10/28/2022]
Abstract
Nicotine replacement treatment (NRT) can be efficacious for smoking cessation, but used by only a minority of smokers in China. Pharmacogenetic matching may improve treatment outcomes for NRT in subgroups of smokers. We evaluated the efficacy and safety of sublingual nicotine tablets (SNT) for smoking cessation and the association of catechol-O-methyltransferase (COMT) genotype with efficacy in this smoking cessation trial among Chinese smokers. We conducted a double-blind, placebo-controlled, 8-week trial of SNT with a follow-up at week 12 among 250 Chinese smokers. Efficacy and safety were evaluated at day 4 and weeks 2, 4, 6, 8, and 12. Abstinence was biochemically verified by exhaled carbon monoxide (CO) and urine cotinine. The COMT Val108Met genotype was determined as a restriction fragment length polymorphism. Our results showed that the success rates for complete abstinence were greater for active versus placebo treatments at 8 weeks (48 vs. 17 %) and 12 weeks (52 vs. 19 %) (both p < 0.0001). Craving was significantly reduced from week 2 on active treatment compared to placebo. Adverse events were mild and tolerable. We found a genotype by treatment interaction at 12 weeks with greater abstinence rates in the COMT Val/Val (50 vs. 15 %) than the Met/Val + Met/Met genotypes (46 vs. 25 %). We found that SNT significantly increased smoking abstinence, reduced craving and was well tolerated, and the COMT Val/Val genotype was associated with a greater improvement in smoking cessation.
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Li WJ, Kou CG, Yu Y, Sun S, Zhang X, Kosten TR, Zhang XY. Association of catechol-O-methyltransferase gene polymorphisms with schizophrenia and negative symptoms in a Chinese population. Am J Med Genet B Neuropsychiatr Genet 2012; 159B:370-5. [PMID: 22354729 PMCID: PMC4190670 DOI: 10.1002/ajmg.b.32038] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 01/31/2012] [Indexed: 12/18/2022]
Abstract
The gene encoding Catechol-O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case-control study of 604 Han Chinese (284 patients and 320 controls). The patients' psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese.
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Affiliation(s)
- Wen Jun Li
- Department of Social Medicine and Health Management, Jilin University, Changchun, China
| | - Chang Gui Kou
- Department of Epidemiology and Health Statistics, Jilin University, Changchun, China
| | - Yaqin Yu
- Research Center for Neuroscience and MH Radiobiology Research Unit, Jilin University, Changchun, China,Corresponding Authors: Yaqin Yu is to be contacted at School of Public Health, Jilin University, Changchun, 130021, China. Tel.: +86 431 85619443. . T.R. Kosten and X.Y. Zhang are to be contacted at VA Medical Center, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel: 7137947032; Fax: 713-794-7938. (T.R. Kosten), (X.Y. Zhang)
| | - Shilong Sun
- Research Center for Neuroscience and MH Radiobiology Research Unit, Jilin University, Changchun, China
| | - Xuan Zhang
- Research Center for Neuroscience and MH Radiobiology Research Unit, Jilin University, Changchun, China
| | - Thomas R Kosten
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA,Psychiatry Research Center, Beijing Hui-Long-Guan Hospital, Beijing, China,Corresponding Authors: Yaqin Yu is to be contacted at School of Public Health, Jilin University, Changchun, 130021, China. Tel.: +86 431 85619443. . T.R. Kosten and X.Y. Zhang are to be contacted at VA Medical Center, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel: 7137947032; Fax: 713-794-7938. (T.R. Kosten), (X.Y. Zhang)
| | - Xiang Yang Zhang
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA,Psychiatry Research Center, Beijing Hui-Long-Guan Hospital, Beijing, China,Corresponding Authors: Yaqin Yu is to be contacted at School of Public Health, Jilin University, Changchun, 130021, China. Tel.: +86 431 85619443. . T.R. Kosten and X.Y. Zhang are to be contacted at VA Medical Center, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel: 7137947032; Fax: 713-794-7938. (T.R. Kosten), (X.Y. Zhang)
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Abstract
Smoking and depression are significant public health problems with multiple etiological dimensions and outcomes. Although each condition is important by itself, they are important because they often potentiate each other. Consequently, it is also essential to understand the nature their relationship. This representative review focuses on the genetic etiology of the relationship in the context of reviewing first the epidemiology of depression and smoking, and then by exploring behavioral and molecular genetic studies, and other psychiatric and medical comorbidities. At this point, epidemiological evidence for a relationship between depression and smoking/nicotine dependence is compelling. Although behavioral genetic results differ somewhat by gender and in accordance with specific definitions of depression and smoking variables, recent studies show converging evidence for common genetic factors underlying the relationship, often in addition to non-shared environmental factors. The search for underlying genes and genetic mechanisms is at an early stage, but shows promising candidate genes and genetic approaches for future studies.
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