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Suresh N, Kantipudi SJ, Ramu D, Muniratnam SK, Venkatesan V. Association between opioid and dopamine receptor gene polymorphisms OPRM1 rs1799971, DAT VNTR 9-10 repeat allele, DRD1 rs4532 and DRD2 rs1799732 and alcohol dependence: an ethnicity oriented meta-analysis. Pharmacogenet Genomics 2023; 33:139-152. [PMID: 37466123 DOI: 10.1097/fpc.0000000000000502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
OBJECTIVE We carried out a meta-analysis of four opioid and dopamine candidate gene polymorphisms having conflicting results in prior literature, namely OPRM1 rs1799971, DAT VNTR 9-10 repeat, DRD1 rs4532 and DRD2 rs1799732, to clarify their association with alcohol dependence and further stratified results by ethnicity to analyze possible ethnicity-mediated effects. METHODS Inclusion criteria: case-control studies assessing the association between OPRM1 rs1799971, DAT VNTR 9/10 repeat allele, DRD1 rs4532 and DRD2 rs1799732 with alcohol dependence, with sufficient data available to calculate the odds ratio (OR) within a 95% confidence interval. Exclusion criteria: studies of quantitative measures of alcohol consumption, response to medications or analyses of other markers in the candidate genes, studies without controls, animal studies and lack of genotyping data. Information sources were PubMed, Google Scholar and ScienceDirect databases, all of which were searched for articles published till 2021. Heterogeneity between studies and publication bias, subgroup analyses and sensitivity analyses were carried out. RESULTS A total of 41 published studies were included in the current meta-analysis. For the OPRM1 gene, there was a statistically significant association in the Asian population with a pooled OR of 1.707 (95% CI, 1.32-2.20 P < 0.0001) and 1.618 (95% CI, 1.16-2.26 P = 0.005) in the additive and dominant genetic models. For DAT VNTR 9/10 repeat, a statistically significant association of the risk vs. common allele was observed in AD with a pooled OR of 1.104 (95% CI, 1.00-1.21 P = 0.046) in the allele model and the additive genetic model in the Caucasian population with pooled OR of 1.152 (95% CI, 1.01-1.31 P = 0.034). CONCLUSION Results indicate that some of the effects may be ethnicity-specific. OTHER The meta-analysis has been registered in the CRD PROSPERO (CRD42023411576).
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Affiliation(s)
| | | | - Deepika Ramu
- Department of Human Genetics SRIHER, Porur, Chennai
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Song S, Marcum CS, Wilkinson AV, Shete S, Koehly LM. Genetic, Psychological, and Personal Network Factors Associated With Changes in Binge Drinking Over 2 Years Among Mexican Heritage Adolescents in the USA. Ann Behav Med 2020; 53:126-137. [PMID: 29697747 DOI: 10.1093/abm/kay019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Despite prevalent binge drinking and alcohol-dependent symptoms among Hispanics, few studies have examined how multidimensional factors influence Hispanic adolescents' binge drinking. Purpose This study examines the effects of genetic, psychological, and social network factors on binge drinking over time among Mexican heritage adolescents in the USA and whether there are correlations among genetic variants that are associated with binge drinking and psychological and network characteristics. Methods Mexican heritage adolescents (n = 731) participated in a longitudinal study, which included genetic testing at baseline, alcohol use assessments at first and second follow-ups, and questionnaires on sensation seeking, impulsivity, and peer and family network characteristics at second follow-up. Logistic regression and Spearman correlation analyses were performed. Results After adjusting for demographic characteristics, underlying genetic clustering, and binge drinking at first follow-up, two genetic variants on tryptophan hydroxylase 2 (TPH2; rs17110451, rs7963717), sensation seeking and impulsivity, and having a greater fraction of peers who drink or encourage drinking alcohol were associated with greater risk whereas another genetic variant on TPH2 (rs11178999) and having a greater fraction of close family relationships were associated with reduced risk for binge drinking at second follow-up. Genetic variants in TPH1 (rs591556) were associated with sensation seeking and impulsivity, while genetic variants in TPH2 (rs17110451) were associated with the fraction of drinkers in family. Conclusions Results reveal that genetic variants in the serotonin pathway, behavioral disinhibition traits, and social networks exert joint influences on binge drinking in Mexican heritage adolescents in the USA.
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Affiliation(s)
- Sunmi Song
- Department of Healthy Living, Health Risk Prevention Team, Korea Health Promotion Institute, Jung-gu, Seoul, Republic of Korea
| | - Christopher Steven Marcum
- Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Anna V Wilkinson
- Department of Epidemiology, Human Genetics and Environmental Science, UTHealth School of Public Health in Austin, Austin, Texas, USA
| | - Sanjay Shete
- Division of Quantitative Sciences, University of Texas MD Anderson Center, Houston, Texas, USA
| | - Laura M Koehly
- Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
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Association between DRD2 and ANKK1 polymorphisms with the deficit syndrome in schizophrenia. Ann Gen Psychiatry 2020; 19:39. [PMID: 32565876 PMCID: PMC7302002 DOI: 10.1186/s12991-020-00289-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 06/11/2020] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The clinical course of schizophrenia varies among patients and is difficult to predict. Some patient populations present persistent negative symptoms, referred to as the deficit syndrome. Compared to relatives of non-deficit schizophrenia patients, family members of this patient population are at an increased risk of developing schizophrenia. Therefore, the aim of this study was to search for genetic underpinnings of the deficit syndrome in schizophrenia. METHODS Three SNPs, i.e., rs1799732 and rs6276 located within DRD2, and rs1800497 within ANKK1, were identified in the DNA samples of 198 schizophrenia probands, including 103 patients with deficit (DS) and 95 patients with non-deficit schizophrenia (NDS). Results: No significant differences concerning any of the analyzed polymorphisms were found between DS and NDS patients. However, significant links were observed between family history of schizophrenia and the deficit syndrome, G/G genotype and rs6276 G allele. In a separate analysis, we identified significant differences in frequencies of rs6276 G allele between DS and NDS patients with family history of schizophrenia. No significant associations were found between DRD2 and ANKK1 SNPs and the age of onset or schizophrenia symptom severity. CONCLUSIONS The results of our preliminary study fail to provide evidence of associations between DRD2 and ANKK1 polymorphisms with the deficit syndrome or schizophrenia symptom severity, but suggest potential links between rs6276 in DRD2 and the deficit syndrome in patients with hereditary susceptibility to schizophrenia. However, further studies are necessary to confirm this observation.
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Jung Y, Montel RA, Shen PH, Mash DC, Goldman D. Assessment of the Association of D2 Dopamine Receptor Gene and Reported Allele Frequencies With Alcohol Use Disorders: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2:e1914940. [PMID: 31702801 PMCID: PMC6902783 DOI: 10.1001/jamanetworkopen.2019.14940] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
IMPORTANCE The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2. OBJECTIVE To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region. DATA SOURCES PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations-Finnish, Native American, and African American participants-were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD. STUDY SELECTION Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies. DATA EXTRACTION AND SYNTHESIS After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. MAIN OUTCOMES AND MEASURES The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data. RESULTS A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I2 = 43%; 95% CI, 23%-58%; Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb the DRD2 transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across the DRD2 region, other SNPs are more strongly associated with AUD than rs1800497, although no DRD2 SNP was significantly associated in these 3 clinical samples. CONCLUSIONS AND RELEVANCE In this meta-analysis, the significant association of DRD2 with AUD was reassessed. The DRD2 association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.
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Affiliation(s)
- Yonwoo Jung
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland
| | - Rachel A. Montel
- Department of Biological Sciences, Seton Hall University, South Orange, New Jersey
| | - Pei-Hong Shen
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland
| | - Deborah C. Mash
- Department of Neurology and Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida
| | - David Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland
- Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland
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Richner KA, Corbin WR, Menary KR. Comparison of subjective response to alcohol in Caucasian and Hispanic/Latino samples. Exp Clin Psychopharmacol 2018; 26:467-475. [PMID: 30035578 PMCID: PMC6162153 DOI: 10.1037/pha0000212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Individual differences in subjective response (SR) to alcohol (e.g., stimulation, sedation) are a significant predictor of negative alcohol outcomes. Previous studies have reported ethnic differences in SR (e.g., between some Asian populations and Caucasians), but very few studies have examined SR among Hispanic/Latino individuals. To address this gap in the literature, the present study utilized data from a large-scale, placebo-controlled alcohol administration study to examine differences in SR between Hispanic/Latino and Caucasian individuals. Social drinkers (N = 447) aged 21 to 25 years were randomized to receive either a dose of alcohol targeting a blood alcohol concentration (BAC) of .08 g% or placebo. Only non-Hispanic Caucasian participants (n = 234) and Hispanic/Latino participants (n = 87) were utilized in analyses. SR was assessed at baseline, on the ascending limb of the blood alcohol curve, at peak BAC, and on the descending limb. Repeated measures ANCOVA was utilized to examine interactions between beverage condition, ethnicity, and time predicting SR. The interaction between beverage condition, ethnicity, and time was significant only for low-arousal negative SR (negative sedative effects), such that Hispanic/Latino individuals experienced stronger sedative effects under alcohol (vs. placebo) compared with Caucasian individuals. Caucasians and Hispanic/Latinos showed a similar profile of response with respect to positive aspects of SR (e.g., stimulation). In summary, Hispanic/Latino individuals reported stronger negative SR to alcohol compared with Caucasian individuals, which may be protective against alcohol-related problems. However, future studies are needed to investigate why Hispanic/Latino males remain at relatively high risk for alcohol problems despite stronger negative SR relative to Caucasians. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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Feistauer V, Vitolo MR, Campagnolo PDB, Mattevi VS, Almeida S. Evaluation of association of DRD2 TaqIA and -141C InsDel polymorphisms with food intake and anthropometric data in children at the first stages of development. Genet Mol Biol 2018; 41:562-569. [PMID: 30044466 PMCID: PMC6136368 DOI: 10.1590/1678-4685-gmb-2017-0202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 01/09/2018] [Indexed: 01/17/2023] Open
Abstract
The reward sensation after food intake may be different between individuals and variants in genes related to the dopaminergic system may indicate a different response in people exposed to the same environmental factors. This study investigated the association of TaqIA (rs1800497) and -141C InsDel (rs1799732) variants in DRD2/ANKK1 gene with food intake and adiposity parameters in a cohort of children. The sample consisted of 270 children followed until 7 to 8 years old. DNA was extracted from blood and polymorphisms were detected by PCR-RFLP analysis. Food intake and nutritional status were compared among individuals with different SNP genotypes. Children carrying the A1 allele (TaqIA) had higher energy of lipid dense foods (LDF) when compared with A2/A2 homozygous children at 7 to 8 years old (GLM p=0.004; Mann Whitney p=0.005). No association was detected with -141C Ins/Del polymorphism. To our knowledge, this is the first association study of the DRD2 TaqIA and -141C Ins/Del polymorphism with food intake and anthropometric parameters in children. DRD2 TaqIA polymorphism has been associated with a reduction in D2 dopamine receptor availability. Therefore, the differences observed in LDF intake in our sample may occur as an effort to compensate the hypodopaminergic functioning.
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Affiliation(s)
- Vanessa Feistauer
- Laboratório de Biologia Molecular, Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Márcia R Vitolo
- Departamento de Saúde Coletiva, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Paula D B Campagnolo
- Curso de Nutrição, Universidade do Vale do Rio dos Sinos, São Leopoldo, RS, Brazil
| | - Vanessa S Mattevi
- Laboratório de Biologia Molecular, Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.,Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Silvana Almeida
- Laboratório de Biologia Molecular, Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.,Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
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Mansoori AA, Jain SK. ADH1B, ALDH2, GSTM1 and GSTT1 Gene Polymorphic Frequencies among Alcoholics and Controls in the Arcadian
Population of Central India. Asian Pac J Cancer Prev 2018; 19:725-731. [PMID: 29582627 PMCID: PMC5980848 DOI: 10.22034/apjcp.2018.19.3.725] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background: Epidemiological research has highlighted the global burden of primary liver cancer cases due to
alcohol consumption, even in a low consumption country like India. Alcohol detoxification is governed by ADH1B,
ALDH2, GSTM1 and GSTT1 genes that encode functional enzymes which are coordinated with each other to remove
highly toxic metabolites i.e. acetaldehyde as well as reactive oxygen species generated through detoxification processes.
Some communities in the population appears to be at greater risk for development of the liver cancer due to genetic
predispositions. Methods: The aim of this study was to screen the arcadian population of central India in order to
investigate and compare the genotype distribution and allele frequencies of alcohol metabolizing genes (ADH1B,
ALDH2, GSTM1 and GSTT1) in both alcoholic (N=121) and control (N=145) healthy subjects. The gene polymorphism
analysis was conducted using PCR and RFLP methods. Results: The allele frequency of ALDH2 *1 was 0.79 and of
ALDH2*2 was 0.21 (OR:1.12; CI (95%): 0.74-1.71). The null allele frequency for GSTM1 was 0.28 (OR:0.85; CI
(95%): 0.50-1.46) and for GSTT1 was 0.20 (OR:1.93; CI (95%): 1.05-3.55). No gene polymorphism for ADH1B was
not observed. The total prevalence of polymorphisms was 3.38% for ALDH2, GSTM1 and GSTT1. Conclusion: The
results of this study suggested that individuals of the Central India population under study are at risk for liver disorders
due to ALDH2, GSTM1 and GSTT1 gene polymorphisms. This results may have significance for prevention of alcohol
dependence, alcoholic liver disorders and the likelihood of liver cancer.
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Affiliation(s)
- Abdul Anvesh Mansoori
- Department of Biotechnology, Dr. Harisingh Gour University, Sagar 470 003 M.P. India.
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Yang HC, Chen IC, Tsay YC, Li ZR, Chen CH, Hwu HG, Chen CH. Using an Event-History with Risk-Free Model to Study the Genetics of Alcoholism. Sci Rep 2017; 7:1975. [PMID: 28512340 PMCID: PMC5434012 DOI: 10.1038/s41598-017-01791-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 04/04/2017] [Indexed: 11/16/2022] Open
Abstract
Case–control genetic association studies typically ignore possible later disease onset in currently healthy subjects and assume that subjects with diseases equally contribute to the likelihood for inference, regardless of their onset age. Therefore, we used an event-history with risk-free model to simultaneously characterize alcoholism susceptibility and onset age in 65 independent non-Hispanic Caucasian males in the Collaborative Study on the Genetics of Alcoholism. Following data quality control, we analysed 22 single nucleotide polymorphisms (SNPs) on 12 candidate genes. The single-SNP analysis showed that the dominant minor allele of rs2134655 on DRD3 increases alcoholism susceptibility; the dominant minor allele of rs1439047 on NTRK2 delays the alcoholism onset age, but the additive minor allele of rs172677 on GRIN2B and the dominant minor allele of rs63319 on ALDH1A1 advance the alcoholism onset age; and the dominant minor allele of rs1079597 on DRD2 shortens the onset age range. Similarly, multiple-SNPs analysis revealed joint effects of rs2134655, rs172677 and rs1079597, with an adjustment for habitual smoking. This study provides a more comprehensive understanding of the genetics of alcoholism than previous case–control studies.
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Affiliation(s)
- Hsin-Chou Yang
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan
| | - I-Chen Chen
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan.,Department of Biostatistics, University of Kentucky, Lexington, KY, 40506, USA
| | - Yuh-Chyuan Tsay
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan
| | - Zheng-Rong Li
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan
| | - Chun-Houh Chen
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan
| | - Hai-Gwo Hwu
- Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.,Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chen-Hsin Chen
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan. .,Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
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Matsushita S, Higuchi S. Review: Use of Asian samples in genetic research of alcohol use disorders: Genetic variation of alcohol metabolizing enzymes and the effects of acetaldehyde. Am J Addict 2017; 26:469-476. [DOI: 10.1111/ajad.12477] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 11/13/2016] [Indexed: 11/30/2022] Open
Affiliation(s)
- Sachio Matsushita
- National Hospital Organization; Kurihama Medical and Addiction Center; Yokosuka Kanagawa Japan
| | - Susumu Higuchi
- National Hospital Organization; Kurihama Medical and Addiction Center; Yokosuka Kanagawa Japan
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Paik SH, Choi MR, Kwak SM, Bang SH, Chun JW, Kim JY, Choi J, Cho H, Jeong JE, Kim DJ. An association study of Taq1A ANKK1 and C957T and - 141C DRD2 polymorphisms in adults with internet gaming disorder: a pilot study. Ann Gen Psychiatry 2017; 16:45. [PMID: 29234453 PMCID: PMC5721653 DOI: 10.1186/s12991-017-0168-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 11/28/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Though Internet gaming disorder (IGD) is considered to share similar genetic vulnerability with substance addictions, little has been explored about the role of the genetic variants on IGD. This pilot study was designed to investigate the association of the Taq1A polymorphism of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene and C957T and - 141C of the dopamine D2 receptor (DRD2) with IGD and their role on the personality and temperament traits in IGD among adult population. METHODS Sixty-three subjects with IGD and 87 control subjects who regularly played Internet games were recruited. Self-administered questionnaires on self-control, dysfunctional impulsivity, and temperament and character domains were done. The Taq1A ANKK1 and the C957T and - 141C ins/del from the DRD2 genes were genotyped using the specific TaqMan PCR assay. RESULTS The distributions of allele and genotype frequencies were not significantly different between the IGD and control groups in both genders. In male, excessive gaming and use of gaming to escape from a negative feeling were associated with the del- genotype of the - 141C. Among IGD, the del+ genotype was associated with higher novelty seeking. Logistic regression showed no predictive value of these polymorphisms for IGD when using age and gender as covariates. CONCLUSIONS Though no direct association of the Taq1A ANKK1 and C957T DRD2 variants with IGD were observed, the - 141C polymorphism may play a role in IGD via mediating symptoms or temperament traits.
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Affiliation(s)
- Soo-Hyun Paik
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Mi Ran Choi
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Su Min Kwak
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Sol Hee Bang
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Ji-Won Chun
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Jin-Young Kim
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Jihye Choi
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Hyun Cho
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Jo-Eun Jeong
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
| | - Dai-Jin Kim
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 222, Banpo-daero, Seocho-gu, Seoul, 06591 South Korea
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Chartier KG, Thomas NS, Kendler KS. Interrelationship between family history of alcoholism and generational status in the prediction of alcohol dependence in US Hispanics. Psychol Med 2017; 47:137-147. [PMID: 27681653 PMCID: PMC5695542 DOI: 10.1017/s0033291716002105] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Both a family history of alcoholism and migration-related factors like US v. foreign nativity increase the risk for developing alcohol use disorders in Hispanic Americans. For this study, we integrated these two lines of research to test whether the relationship between familial alcoholism and alcohol dependence changes with successive generations in the United States. METHOD Data were from the waves 1 and 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Subjects self-identified Hispanic ethnicity (N = 4122; n = 1784 first, n = 1169 second, and n = 1169 third or later generation) and reported ever consuming ⩾12 drinks in a 1-year period. A family history of alcoholism was assessed in first- and second-degree relatives. Analyses predicting the number of alcohol dependence symptoms were path models. RESULTS Alcohol dependence symptoms were associated with a stronger family history of alcoholism and later generational status. There was a significant interaction effect between familial alcoholism and generational status; the relationship of familial alcoholism with alcohol dependence symptoms increased significantly with successive generations in the United States, more strongly in women than men. Acculturation partially mediated the interaction effect between familial alcoholism and generational status on alcohol dependence, although not in the expected direction. CONCLUSIONS Familial alcoholism interacted with generational status in predicting alcohol dependence symptoms in US Hispanic drinkers. This relationship suggests that heritability for alcoholism is influenced by a higher-order environmental factor, likely characterized by a relaxing of social restrictions on drinking.
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Affiliation(s)
- Karen G. Chartier
- Virginia Commonwealth University School of Social Work, Richmond, VA
- Virginia Commonwealth University School of Medicine, Department of Psychiatry, Richmond, VA
| | | | - Kenneth S. Kendler
- Virginia Commonwealth University School of Medicine, Department of Psychiatry, Richmond, VA
- Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA
- Virginia Commonwealth University School of Medicine, Department of Human and Molecular Genetics, Richmond, VA
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Chartier KG, Dick DM, Almasy L, Chan G, Aliev F, Schuckit MA, Scott DM, Kramer J, Bucholz KK, Bierut LJ, Nurnberger J, Porjesz B, Hesselbrock VM. Interactions Between Alcohol Metabolism Genes and Religious Involvement in Association With Maximum Drinks and Alcohol Dependence Symptoms. J Stud Alcohol Drugs 2016; 77:393-404. [PMID: 27172571 PMCID: PMC4869897 DOI: 10.15288/jsad.2016.77.393] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 11/06/2015] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes. METHOD Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1Brs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance. RESULTS Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement. CONCLUSIONS This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.
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Affiliation(s)
- Karen G. Chartier
- Virginia Commonwealth University School of Social Work, Richmond, Virginia
- Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Danielle M. Dick
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Laura Almasy
- South Texas Diabetes and Obesity Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Grace Chan
- Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Fazil Aliev
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia
- Faculty of Business, Karabuk University, Karabuk, Turkey
| | - Marc A. Schuckit
- Department of Psychiatry, University of San Diego School of Medicine, La Jolla, California
| | - Denise M. Scott
- Departments of Pediatrics and Human Genetics, Howard University, Washington, DC
| | - John Kramer
- Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Kathleen K. Bucholz
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
| | - Laura J. Bierut
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
| | - John Nurnberger
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana
| | - Bernice Porjesz
- Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, New York
| | - Victor M. Hesselbrock
- Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut
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A review of 5-HT transporter linked promoter region (5-HTTLPR) polymorphism and associations with alcohol use problems and sexual risk behaviors. J Community Genet 2016; 7:1-10. [PMID: 26338666 PMCID: PMC4715809 DOI: 10.1007/s12687-015-0253-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 08/27/2015] [Indexed: 01/05/2023] Open
Abstract
Alcohol use and sexual risk behaviors are multidimensional phenomena involving many genetic and environmental factors. 5-HT transporter linked promoter region (5-HTTLPR) polymorphism constitutes an important factor affecting alcohol use problems and risky sexual behaviors. This paper narratively reviews studies on 5-HTTLPR polymorphism and its associations with alcohol use problems and sexual risk behaviors. We searched the electronic databases, PubMed, Ovid, and Google Scholar for articles using MeSH terms. Relevant articles were reviewed and eligible articles were selected for the study. Many studies have reported a significant but moderate association between 5-HTTLPR polymorphism and alcohol use problems. These studies have implicated the presence of at least one S allele to be associated with significant increases in alcohol use problems. Similarly, some studies associate the S allele with increased sexual risk behaviors. Effective alcohol cessation initiatives and STI/HIV prevention programs should be modified to account for 5-HTTLPR polymorphism before planning interventions; genetic effects could moderate the intervention effect.
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A meta-analysis of the associations between the SLC6A4 promoter polymorphism (5HTTLPR) and the risk for alcohol dependence. Psychiatr Genet 2015; 25:47-58. [PMID: 25710844 DOI: 10.1097/ypg.0000000000000078] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Serotonin reuptake variation is linked to a functional polymorphism in the promoter region of the SLC6A4 gene on chromosome 17. It is plausible that variations in genetically determined SLC6A4 activity may modify the risk for alcohol dependence. To determine whether this allele is associated with alcohol dependence, the authors conducted a systematic review and meta-analysis. Twenty-five studies including 8885 participants were reviewed and analyzed. The meta-analysis was carried out using a random-effects model. Overall, the results did not support an association between alcohol dependence and the SLC6A4 promoter polymorphism for the dominant, recessive, and additive genetic risk models, respectively [odds ratio (OR)=0.99 (95% confidence interval (CI): 0.83, 1.18), OR=0.86 (95% CI: 0.71, 1.03), and OR=0.88 (95% CI: 0.69, 1.13)]. When effect modification was tested for sex, race/ethnicity, presence/absence of a psychiatric disorder, year of publication, and diagnostic criteria, none of the factors were found to be significantly associated with alcohol dependence. The findings in this meta-analysis suggest that the SLC6A4 promoter polymorphism is not associated with alcohol dependence.
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Ayhan Y, Gürel ŞC, Karaca Ö, Zoto T, Hayran M, Babaoğlu M, Yaşar Ü, Bozkurt A, Dilbaz N, Uluğ BD, Demir B. Association between ADH1C and ALDH2 polymorphisms and alcoholism in a Turkish sample. Nord J Psychiatry 2015; 69:233-9. [PMID: 25372623 DOI: 10.3109/08039488.2014.972450] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Polymorphisms in the genes encoding alcohol metabolizing enzymes are associated with alcohol dependence. AIM To evaluate the association between the alcohol dehydrogenase 1C (ADH1C) Ile350Val and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphisms and alcohol dependence in a Turkish sample. METHODS 235 individuals (115 alcohol-dependent patients and 120 controls) were genotyped for ADH1C and ALDH2 with PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Association between the polymorphisms and family history, daily and maximum amount of alcohol consumed was investigated. The associations between alcohol dependence, severity of consumption and family history and the polymorphisms were analyzed by chi-square or Fisher's exact test where necessary. Relationship between genotypes and dependence related features was evaluated using analysis of variance (ANOVA). RESULTS The -350Val allele for ADH1C (ADH1C*2) was increased in alcohol-dependent patients (P = 0.05). In individuals with a positive family history, the genotype distribution differed significantly (P = 0.031) and more patients carried the Val allele compared with controls (P = 0.025). Genotyping of 162 participants did not reveal the -504Lys allele in ALDH2. CONCLUSIONS These findings suggest that ADH1C*2 is associated with alcohol dependence in the Turkish population displaying a dominant inheritance model. ADH1C*2 allele may contribute to the variance in heritability of alcohol dependence. The ALDH2 -504Lys/Lys or Glu/Lys genotypes were not present in alcohol-dependent patients, similar to that seen in European populations and in contrast to the findings in the Asian populations.
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Affiliation(s)
- Yavuz Ayhan
- Yavuz Ayhan, Hacettepe University, Faculty of Medicine, Department of Psychiatry , 06100, Sıhhiye, Ankara , Turkey
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Norden-Krichmar TM, Gizer IR, Wilhelmsen KC, Schork NJ, Ehlers CL. Protective variant associated with alcohol dependence in a Mexican American cohort. BMC MEDICAL GENETICS 2014; 15:136. [PMID: 25527893 PMCID: PMC4337107 DOI: 10.1186/s12881-014-0136-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 12/08/2014] [Indexed: 01/11/2023]
Abstract
Background Mexican Americans, particularly those born in the United States, are at greater risk for alcohol associated morbidity and mortality. The present study sought to investigate whether specific genetic variants may be associated with alcohol use disorder phenotypes in a select population of Mexican American young adults. Methods The study evaluated a cohort of 427 (age 18 – 30 years) Mexican American men (n = 171) and women (n = 256). Information on alcohol dependence was obtained through interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). For all subjects, DNA was extracted from blood samples, followed by genotyping using an Affymetrix Axiom Exome1A chip. Results A protective variant (rs991316) located downstream from the ADH7 (alcohol dehydrogenase 7) gene showed suggestive significance in association with alcohol dependence symptom counts derived from DSM-III-R and DSM-IV criteria, as well as to clustered alcohol dependence symptoms. Additional linkage analysis suggested that nearby variants in linkage disequilibrium with rs991316 were not responsible for the observed association with the alcohol dependence phenotypes in this study. Conclusions ADH7 has been shown to have a protective role against alcohol dependence in previous studies involving other ethnicities, but has not been reported for Mexican Americans. These results suggest that variants near ADH7 may play a role in protection from alcohol dependence in this Mexican American cohort.
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Montane Jaime LK, Shafe S, Liang T, Wills DN, Berg GI, Ehlers CL. Subjective response to alcohol and ADH polymorphisms in a select sample of young adult male East Indians and Africans in Trinidad and Tobago. J Stud Alcohol Drugs 2014; 75:827-38. [PMID: 25208201 PMCID: PMC4161702 DOI: 10.15288/jsad.2014.75.827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 04/29/2014] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Level of response to alcohol has been associated with risk of alcohol dependence in a number of ethnic groups. In the present study, subjective and objective responses to alcohol were evaluated in Indo-Trinidadians (Indo-T) and Afro-Trinidadians (Afro-T). Associations of alcohol dehydrogenase polymorphisms with response to alcohol, using the Subjective High Assessment Scale (SHAS), and breath alcohol concentrations (BrAC) were tested. METHOD Regular male drinkers without alcohol dependence (n = 112) ages 18-25 years participated in alcohol challenge sessions consisting of placebo and two doses of alcohol (target BrAC: 0 g/dl for placebo, .04 g/dl low dose, and .08 g/dl high dose) and genotyped for variants in ADH1B*3 and ADH1C*2. RESULTS Indo-T had significantly higher BrAC, pulse rates, and cortisol levels when compared with Afro-T but did not have significantly higher SHAS values. Higher responses on the SHAS items muddle/confused and nauseated were significantly associated with the presence of at least one ADH1B*3 allele following the high dose of alcohol in Afro-T. Indo-T with at least one ADH1C*2 allele displayed significantly different Drug × Time interactions for the SHAS item effects of alcohol at the low dose and for the SHAS items clumsy, muddle/confused, effects of alcohol, floating, drunk, and total at the high dose from Indo-T with two ADH1C*1 alleles. CONCLUSIONS This is the first study that has investigated individual sensitivity to alcohol in a Caribbean population and in people of East Indian descent. Indo-T with at least one ADH1C*2 allele may be at higher risk for heavy drinking by feeling less of the effects of alcohol, including nausea. In Afro-T, having at least one ADH1B*3 allele appears to exert a protective effect by enhancing the unpleasant effects of alcohol, such as nausea and confusion.
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Affiliation(s)
- Lazara Karelia Montane Jaime
- Pharmacology Unit, Department of Paraclinical Sciences, Faculty of Medical Sciences, University of the West Indies, St. Augustine, Trinidad and Tobago
| | - Samuel Shafe
- Psychiatric Unit, Department of Clinical Sciences, Faculty of Medical Sciences, University of the West Indies, St. Augustine, Trinidad and Tobago
| | - Tiebing Liang
- Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Derek N Wills
- Department of Molecular and Cellular Neurosciences, Scripps Research Institute, La Jolla, California
| | - Greta I Berg
- Department of Molecular and Cellular Neurosciences, Scripps Research Institute, La Jolla, California
| | - Cindy L Ehlers
- Department of Molecular and Cellular Neurosciences, Scripps Research Institute, La Jolla, California
- Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California
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Sosa-Macías M, Llerena A. Cytochrome P450 genetic polymorphisms of Mexican indigenous populations. ACTA ACUST UNITED AC 2014; 28:193-208. [PMID: 24145057 DOI: 10.1515/dmdi-2013-0037] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/02/2013] [Indexed: 11/15/2022]
Abstract
This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic (CYP2D6, CYP2C9) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1, and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose *1F variant frequency in Mexican Amerindians was the highest described to date.
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Banerjee N. Neurotransmitters in alcoholism: A review of neurobiological and genetic studies. INDIAN JOURNAL OF HUMAN GENETICS 2014; 20:20-31. [PMID: 24959010 PMCID: PMC4065474 DOI: 10.4103/0971-6866.132750] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Recent advances in the study of alcoholism have thrown light on the involvement of various neurotransmitters in the phenomenon of alcohol addiction. Various neurotransmitters have been implicated in alcohol addiction due to their imbalance in the brain, which could be either due to their excess activity or inhibition. This review paper aims to consolidate and to summarize some of the recent papers which have been published in this regard. The review paper will give an overview of the neurobiology of alcohol addiction, followed by detailed reviews of some of the recent papers published in the context of the genetics of alcohol addiction. Furthermore, the author hopes that the present text will be found useful to novices and experts alike in the field of neurotransmitters in alcoholism.
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Affiliation(s)
- Niladri Banerjee
- Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
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Matsushita S, Higuchi S. Genetic differences in response to alcohol. HANDBOOK OF CLINICAL NEUROLOGY 2014; 125:617-27. [PMID: 25307600 DOI: 10.1016/b978-0-444-62619-6.00036-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The level of response to alcohol, which reflects individual differences in sensitivity to the pharmacologic effects of alcohol, is considered to be an important endophenotype of alcohol use disorder (AUD). By comparing monozygotic and dizygotic twins, the heritability of the level of response to alcohol has been estimated to be 60%. Many genes have been implicated as potential contributors toward heavy drinking, alcohol-related problems, and AUD through a low level of response to alcohol, each with a small effect. Identified are genes for gamma-aminobutyric acid (GABA) receptors, serotonin transporter, opioid receptor, and nicotinic acetylcholine receptor, but the most well-characterized genes that have a strong impact on the level of response to alcohol are those for alcohol-metabolizing enzymes. Although two genetic variations in alcohol and aldehyde dehydrogenases, which have been the most intensively studied, exist almost exclusively in Asian populations, studies on the effect of genetic variations in alcohol-metabolizing enzymes on the response to alcohol are gradually expanding in non-Asian populations. In this chapter, we focus on genetic studies in humans. After analyzing the overall influence of genetic factors on the response to alcohol, we explore individual genes that may influence the response to alcohol. Lastly, we review studies examining the effects of genetic variations in alcohol-metabolizing enzymes on the level of response to alcohol.
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Affiliation(s)
- Sachio Matsushita
- National Hospital Organization, Kurihama Medical and Addiction Center, Kanagawa, Japan.
| | - Susumu Higuchi
- National Hospital Organization, Kurihama Medical and Addiction Center, Kanagawa, Japan
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Sallée M, Fontès M, Louis L, Cérini C, Brunet P, Burtey S. Alternative splicing events is not a key event for gene expression regulation in uremia. PLoS One 2013; 8:e82702. [PMID: 24358217 PMCID: PMC3865105 DOI: 10.1371/journal.pone.0082702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 10/26/2013] [Indexed: 11/29/2022] Open
Abstract
Background The control of gene expression in the course of chronic kidney disease (CKD) is not well addressed. Alternative splicing is a common way to increase complexity of proteins. More than 90% of human transcripts are alternatively spliced. We hypothesised that CKD can induce modification of the alternative splicing machinery. Methods During mutation screening in autosomal dominant polycystic kidney disease, we identified in mononuclear cells (PBMC), an alternative splicing event on the exon 30 of PKD1 gene, the gene implicated in this disease. This alternative splice variant was not correlated with the cystic disease but with CKD. To confirm the association between this variant and CKD, a monocentric clinical study was performed with 3 different groups according to their kidney function (CKD5D, CKD3-5 and normal kidney function). An exon microarray approach was used to highlight splicing events in whole human genome in a normal cell model (fibroblasts) incubated with uremic serum. Alternative splicing variants identified were confirmed by RT-PCR. Results The splicing variant of the exon 30 of PKD1 was more frequent in PBMCs from patients with CKD compared to control. With the microarray approach, despite the analysis of more than 230 000 probes, we identified 36 genes with an abnormal splicing index evocating splicing event in fibroblasts exposed to uremic serum. Only one abnormal splicing event in one gene, ADH1B, was confirmed by RT-PCR. Conclusion We observed two alternative spliced genes in two different cell types associated with CKD. Alternative splicing could play a role in the control of gene expression during CKD but it does not seem to be a major mechanism.
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Affiliation(s)
- Marion Sallée
- Aix-Marseille Université, INSERM UMR_S 1076, UFR Pharmacie, Marseille, France ; Centre de Néphrologie et Transplantation Rénale, Assistance Publique-Hôpitaux de Marseille, Hôpital de La Conception, Marseille, France
| | - Michel Fontès
- Aix-Marseille Université, INSERM UMR_S 1062 UFR Médecine, Marseille, France
| | - Laurence Louis
- Aix-Marseille Université, Plate-forme génomique et transcriptomique, UMR_S 910, UFR médecine, Marseille, France
| | - Claire Cérini
- Aix-Marseille Université, INSERM UMR_S 1076, UFR Pharmacie, Marseille, France
| | - Philippe Brunet
- Aix-Marseille Université, INSERM UMR_S 1076, UFR Pharmacie, Marseille, France ; Centre de Néphrologie et Transplantation Rénale, Assistance Publique-Hôpitaux de Marseille, Hôpital de La Conception, Marseille, France
| | - Stéphane Burtey
- Aix-Marseille Université, INSERM UMR_S 1076, UFR Pharmacie, Marseille, France ; Centre de Néphrologie et Transplantation Rénale, Assistance Publique-Hôpitaux de Marseille, Hôpital de La Conception, Marseille, France
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Cao J, Hudziak JJ, Li D. Multi-cultural association of the serotonin transporter gene (SLC6A4) with substance use disorder. Neuropsychopharmacology 2013; 38:1737-47. [PMID: 23518607 PMCID: PMC3717550 DOI: 10.1038/npp.2013.73] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 03/18/2013] [Accepted: 03/19/2013] [Indexed: 01/06/2023]
Abstract
A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition. This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder. The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR)=0.54 (0.35, 0.84); 0.0024 with OR=0.77 (0.66, 0.91); 0.018 with OR=1.38 (1.06, 1.81); and 0.028 with OR=0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively). When all the phenotypes are combined, the P-value was 0.0006 with OR=0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR=1.41 (1.13, 1.78) in the African populations. Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence. This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.
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Affiliation(s)
- Jian Cao
- Department of Pathology, School of Medicine, Yale University, New Haven, CT, USA
| | - James J Hudziak
- Vermont Center for Children, Youth, and Families, Department of Psychiatry, University of Vermont, Burlington, VT, USA
| | - Dawei Li
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, USA
- Neuroscience, Behavior, and Health Initiative, University of Vermont, Burlington, VT, USA
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Lee SH, Lee BH, Lee JS, Chai YG, Choi MR, Han DMR, Ji H, Jang GH, Shin HE, Choi IG. The Association of DRD2 −141C and ANKK1 TaqIA Polymorphisms with Alcohol Dependence in Korean Population Classified by the Lesch Typology. Alcohol Alcohol 2013; 48:426-32. [DOI: 10.1093/alcalc/agt029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Suraj Singh H, Ghosh PK, Saraswathy KN. DRD2 and ANKK1 gene polymorphisms and alcohol dependence: a case-control study among a Mendelian population of East Asian ancestry. Alcohol Alcohol 2013; 48:409-14. [PMID: 23443985 DOI: 10.1093/alcalc/agt014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS Dopamine receptors are extensively studied in association with alcohol dependence (AD), since they are thought to be the key neural substrate for alcohol and other drug-related reinforcement and reward behaviours. The present study aims to understand the role of dopamine receptors in susceptibility to AD with respect to three sites of DRD2 gene (-141C Ins/Del, TaqIB and TaqID) and TaqIA site of ANKK1 gene among Meiteis of Manipur, a Mendelian population of India. METHODS A total of 129 individuals who all met the DSM-IV criteria for AD and 286 controls were screened for four single-nucleotide polymorphisms (SNPs) -141C Ins/Del, TaqIB TaqID and TaqIA. Both AD cases and controls were unrelated up to first cousin. RESULTS Early age of onset of alcohol consumption and smoking status were significantly associated with AD. Improvement in education and occupation statuses showed decreased risk of AD. The heterozygous and mutant homozygous conditions of ANKK1 TaqIA polymorphism were found to be significantly associated with AD (odds ratio = 2.13, 95% confidential interval 1.04-4.39, P < 0.05), whereas a borderline significance of the -141C Del allele was observed (P = 0.059). Such a trend was not observed between AD and the other polymorphism, i.e., TaqIB and TaqID. CONCLUSIONS Individuals carrying the A1 allele of ANKK1 TaqIA polymorphism may be relatively more susceptible to AD. Interaction of both ANKK1 TaqIA and -141C Ins/Del polymorphism is likely to increase risk of AD phenotypes among Meiteis of Manipur, India.
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Affiliation(s)
- Huidrom Suraj Singh
- Molecular Anthropology Laboratory, Department of Anthropology, University of Delhi, Delhi 110007, India
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Ehlers CL, Liang T, Gizer IR. ADH and ALDH polymorphisms and alcohol dependence in Mexican and Native Americans. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2013; 38:389-94. [PMID: 22931071 DOI: 10.3109/00952990.2012.694526] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Ethanol is primarily metabolized in the liver by two rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. OBJECTIVES AND METHODS Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2 were compared in a community sample of Native Americans (n 791) living on reservations and Mexican Americans (n 391) living within the same county. RESULTS Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% of the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations.
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Affiliation(s)
- Cindy L Ehlers
- Department of Molecular and Integrative Neurosciences, The Scripps Research Institute , La Jolla, CA 92037, USA.
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Wang F, Simen A, Arias A, Lu QW, Zhang H. A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence. Hum Genet 2012. [PMID: 23203481 DOI: 10.1007/s00439-012-1251-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Alcohol dependence (AD) is a common neuropsychiatric disorder with high heritability. A number of studies have analyzed the association between the Taq1A polymorphism (located in the gene cluster ANKK1/DRD2) and AD. In the present study, we conducted a large-scale meta-analysis to confirm the association between the Taq1A polymorphism and the risk for AD in over 18,000 subjects included in 61 case-control studies that were published up to August 2012. Our meta-analysis demonstrated both allelic and genotypic association between the Taq1A polymorphism and AD susceptibility [allelic: P(Z) = 1.1 × 10(-5), OR = 1.19; genotypic: P(Z) = 3.2 × 10(-5), OR = 1.24]. The association remained significant after adjustment for publication bias using the trim and fill method. Sensitivity analysis showed that the effect size of the Taq1A polymorphism on AD risk was moderate and not influenced by any individual study. The pooled odds ratio from published studies decreased with the year of publication, but stabilized after the year 2001. Subgroup analysis indicated that publication bias could be influenced by racial ancestry. In summary, this large-scale meta-analysis confirmed the association between the Taq1A polymorphism and AD. Future studies are required to investigate the functional significance of the ANKK1/DRD2 Taq1A polymorphism in AD.
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Affiliation(s)
- Fan Wang
- Department of Psychiatry, Yale University School of Medicine, VA Medical Center/116A2, 950 Campbell Avenue, West Haven, CT 06516, USA
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Wei YM, Du YL, Nie YQ, Li YY, Wan YJY. Nur-related receptor 1 gene polymorphisms and alcohol dependence in Mexican Americans. World J Gastroenterol 2012; 18:5276-82. [PMID: 23066323 PMCID: PMC3468861 DOI: 10.3748/wjg.v18.i37.5276] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 05/18/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association of polymorphisms of nur-related receptor 1 (Nurr1) and development of alcohol dependence in Mexican Americans.
METHODS: Peripheral blood samples were collected from 374 alcoholic and 346 nonalcoholic Mexican Americans; these two groups were sex- and age-matched. Sample DNA was extracted and genomic DNA was amplified by polymerase chain reaction. The -2922(C) 2-3 polymerase chain reaction products were digested with Sau96I, alleles of 1345(G/C), and -1198(C/G) in the regulatory region as well as Ex+132 (G/T/A/C) and Ex+715(T/-) in exon 3 were studied by sequencing.
RESULTS: The C2/C2, C2/C3, C3/C3 genotype distribution of -2922(C) 2-3 was 34.4%, 38.2% and 27.5% in the nonalcoholic group compared to 23.3%, 51.2% and 25.4% in the alcoholic group (P = 0.001). The C/C, C/G, G/G genotype distribution of -1198(C/G) was 23.5%, 46.1% and 30.3% in the nonalcoholic group compared to 13.9%, 50.9% and 35.3% in the alcoholic group (P = 0.007). However, the -1345 (G/C), Ex3+132(G/T/A/C) and Ex3+715(T/-) alleles were not polymorphic in Mexican Americans, and all those studied had G/G, G/G and T/T genotype for these three alleles, respectively. The -2922(C) 2-3 did not show allele level difference between alcoholic and nonalcoholic individuals, but -1198 (C/G) showed a significant allele frequency difference between alcoholic (39.3%) and nonalcoholic (46.6%) populations (P = 0.005). Excluding obese individuals, significant differences were found at both genotypic and allelic levels for the -2922(C) 2-3 polymorphism (P = 0.000 and P = 0.049) and the -1198 (C/G) polymorphism (P = 0.008 and P = 0.032) between nonobese alcoholics and nonobese controls. Excluding smokers, a significant difference was found only at the genotypic level for the -2922(C) 2-3 polymorphism (P = 0.037) between nonsmoking alcoholics and nonsmoking controls, but only at the allelic level for the -1198(C/G) polymorphism (P = 0.034).
CONCLUSION: Polymorphisms in the regulatory region of Nurr1 are implicated in pathogenesis of alcohol dependence and the Nurr1/dopamine signaling pathway might be important for this dependence development in Mexican Americans.
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Jacob C. Peter Riederer "70th birthday" neurobiological foundations of modern addiction treatment. J Neural Transm (Vienna) 2012; 120:55-64. [PMID: 22903349 DOI: 10.1007/s00702-012-0886-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 07/31/2012] [Indexed: 11/29/2022]
Abstract
Alcohol dependence is caused by complex interactions of multiple susceptibility genes with little effect each and environmental factors. Candidate genes influence metabolism of alcohol, such as alcohol dehydrogenase and aldehyde dehydrogenase, and modulatory transmitter systems, such as the dopaminergic, serotonergic, acetylcholinergic, gamma-aminobutyric acidergic, and various neuropeptidergic systems. Dysfunctional behavioral choices, learning, and memory are involved in the etiology of alcohol dependence. Systematic promotion and maintenance of motivation is a lifetime challenge in the treatment of alcohol use disorders. The second step of treatment management is the discontinuation of alcohol consumption. Withdrawal symptoms can be treated with gamma-aminobutyric acidergic substances such as benzodiazepines. Long-term relapse prevention is another challenge. Multimodal treatment can include naltrexone, a non-selective opioid receptor antagonist, or acamprosate, an N-methyl-D-aspartate receptor modulator, which are first line for pharmacological treatment on the basis of recent Cochrane analyses. Due to the complexity of etiology with both psychological and neurobiological factors, future treatment management of alcoholism may include the combination of individualized disorder-specific psychotherapy and drugs acting on different neuronal pathways, on the basis of individual vulnerability. However, the question remains unsolved whether an individualized approach is feasible and how subgroups should be defined.
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Affiliation(s)
- Christian Jacob
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080, Wuerzburg, Germany.
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Li D, Zhao H, Gelernter J. Further clarification of the contribution of the ADH1C gene to vulnerability of alcoholism and selected liver diseases. Hum Genet 2012; 131:1361-74. [PMID: 22476623 PMCID: PMC3557796 DOI: 10.1007/s00439-012-1163-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 03/24/2012] [Indexed: 12/13/2022]
Abstract
The alcohol dehydrogenase 1C (ADH1C) subunit is an important member of the alcohol dehydrogenase family, a set of genes that plays a major role in the catabolism of ethanol. Numerous association studies have provided compelling evidence that ADH1C gene variation (formerly ADH3) is associated with altered genetic susceptibility to alcoholism and alcohol-related liver disease, cirrhosis, or pancreatitis. However, the results have been inconsistent, partially, because each study involved a limited number of subjects, and some were underpowered. Using cumulative data over the past two decades, this meta-analysis (6,796 cases and 6,938 controls) considered samples of Asian, European, African, and Native American origins to examine whether the aggregate genotype provide statistically significant evidence of association. The results showed strong evidence of association between ADH1C Ile350Val (rs698, formerly ADH1C *1/*2) and alcohol dependence (AD) and abuse in the combined studies. The overall allelic (Val vs. Ile or *2 vs. *1) P value was 1 × 10(-8) and odds ratio (OR) was 1.51 (1.31, 1.73). The Asian populations produced stronger evidence of association with an allelic P value of 4 × 10(-33) [OR 2.14 (1.89, 2.43)] with no evidence of heterogeneity, and the dominant and recessive models revealed even stronger effect sizes. The strong evidence remained when stricter criteria and sub-group analyses were applied, while Asians always showed stronger associations than other populations. Our findings support that ADH1C Ile may lower the risk of AD and alcohol abuse as well as alcohol-related cirrhosis in pooled populations, with the strongest and most consistent effects in Asians.
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Affiliation(s)
- Dawei Li
- Department of Psychiatry, School of Medicine, Yale University, 300 George Street, Suite 503, New Haven, CT 06511, USA.
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Li D, Zhao H, Gelernter J. Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet 2012; 131:725-37. [PMID: 22102315 PMCID: PMC3548401 DOI: 10.1007/s00439-011-1116-4] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 11/12/2011] [Indexed: 12/20/2022]
Abstract
Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case-control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 × 10(-56) and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys-lys + lys-glu vs. glu-glu) also showed strong association with P value of 1 × 10(-44) and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2 × 10(-28) for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians.
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Affiliation(s)
- Dawei Li
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06511, USA.
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Li D, Zhao H, Gelernter J. Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases. Biol Psychiatry 2011; 70:504-12. [PMID: 21497796 PMCID: PMC3142297 DOI: 10.1016/j.biopsych.2011.02.024] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 02/21/2011] [Accepted: 02/21/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND The alcohol dehydrogenase 1B gene (ADH1B) is hypothesized to affect predisposition to alcohol dependence (AD) and abuse. A variant of the ADH1B gene (rs1229984 or Arg48His; previously referred to as Arg [*1] and His [*1]) has been reported to be associated with reduced rates of alcohol and drug dependence. Different studies have produced inconclusive results regarding association between rs1229984 (or rs2066702) and substance dependence. METHODS Using the cumulative association study literature from the past 21 years from both English- and Chinese-language publications, this meta-analysis seeks to clarify the contradictory findings and to examine whether the aggregate data provide new evidence of significant association. RESULTS The results, based on a large sample size (9638 cases and 9517 controls), suggested strong associations with alcohol dependence and abuse as well as alcohol-induced liver diseases, with an allelic (Arg vs. His) p value being 1 × 10(-36) and odds ratio (OR) (95% confidence intervals [CI]) 2.06 (1.84-2.31) under the random effects model. The dominant and recessive models produced larger ORs of 2.17 and 3.05, respectively. When more stringent criteria and subgroup analyses were imposed, the associations remained consistent and were strongest in various Asian groups (allelic p = 7 × 10(-42) and OR (95% CI) = 2.24 [1.99-2.51] with ORs of 2.16 and 4.11 for dominant and recessive models, respectively). CONCLUSIONS Our findings provide further strong evidence for the involvement of the ADH1B gene in the pathogenesis of alcohol dependence and abuse as well as for some alcohol-induced medical diseases in the multiple ethnic populations--in particular, certain Asian populations.
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Affiliation(s)
- Dawei Li
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06511, USA.
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Wang XJ, Zhong SR, Bao JJ, Dou SJ, Wu WY, Jing Q. [Association of polymorphism in the serotonin transporter gene promote with the susceptibility to alcohol dependence in Yunnan Han Population]. YI CHUAN = HEREDITAS 2011; 33:48-53. [PMID: 21377958 DOI: 10.3724/sp.j.1005.2011.00048] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
To explore the association of polymorphism in the serotonin transporter gene and the susceptibility to alcohol dependence in Yunnan Han population, PCR and DNA sequencing techniques were used to detect 5-HTT-linked promoter region (5-HTTLPR). One hundred and eighteen alcohol dependent patients as case group and 214 normal people as control group were employed in this study. Significant differences in genotype frequencies were present between case group and control group of 5-HTTLPR (P<0.05). The proportion of L/L and L/S genotype was significantly smaller in case group than that was in control group (OR=0.581, P=0.026). No significant association was observed in allelic frequencies, which differed in different ethnic groups. In conclusion, 5-HTTLPR polymorphism may be associated with alcohol dependent patients, and the genotype L/L or L/S may be a genetic factor that is responsible for decreasing susceptibility of alcohol dependence in Yunnan Han population.
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Affiliation(s)
- Xue-Jing Wang
- Department of Forensic Medicine, Kunming Medical University, Kunming 650500, China.
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Abstract
Twin, family, and adoption studies have consistently shown that genetic factors play an important role in the pathogenesis of alcohol dependence. Numerous studies have aimed to identify genes that contribute to susceptibility to alcohol dependence. Whole-genome linkage studies have identified several chromosomal regions that are linked with alcohol dependence. Association studies have also identified genes associated with alcohol dependence. Alcohol-metabolizing enzymes, such as alcohol dehydrogenase-1B and aldehyde dehydrogenase-2, are the most well-established genes that have polymorphisms associated with the risk for alcohol dependence. Polymorphisms in gamma-aminobutyric acid receptor genes are also reported to be associated with alcohol dependence. The polymorphism of opioid receptor mu 1 gene is of interest because it alters the treatment effects of naltrexone. Several genes related to neural transmission have been reported to be associated with alcohol dependence, but results are inconsistent among studies. One reason for these inconsistent results is the great heterogeneity of alcohol dependence. Classifying alcohol dependence into homogeneous phenotypes is a good strategy to solve this problem. Recently, several genome-wide association studies have been reported. Genome-wide association studies enable hypothesis-free genome mapping of vulnerability-contributing genes and are expected to add data to identify genes associated with the susceptibility to alcohol dependence. Knowledge of the genetic basis of alcohol dependence is growing and leads to a better understanding of the biological mechanisms of addiction, which can help with strategies to prevent and treat this disease.
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Affiliation(s)
- Mitsuru Kimura
- National Hospital Organization, Kurihama Alcoholism Center, Kanagawa, Japan.
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Gyamfi MA, Wan YJY. Pathogenesis of alcoholic liver disease: the role of nuclear receptors. Exp Biol Med (Maywood) 2010; 235:547-60. [PMID: 20463294 DOI: 10.1258/ebm.2009.009249] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor alpha and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD). Given their pivotal roles in physiological processes, NRs represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases including ALD. This review summarizes the factors that contribute to ALD and the molecular mechanisms of ALD with a focus on the role of NRs.
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Affiliation(s)
- Maxwell Afari Gyamfi
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, Kansas 66160-7417, USA
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Prasad P, Ambekar A, Vaswani M. Dopamine D2 receptor polymorphisms and susceptibility to alcohol dependence in Indian males: a preliminary study. BMC MEDICAL GENETICS 2010; 11:24. [PMID: 20146828 PMCID: PMC2829542 DOI: 10.1186/1471-2350-11-24] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Accepted: 02/11/2010] [Indexed: 12/13/2022]
Abstract
Background Dopamine is an important neurotransmitter involved in reward mechanism in the brain and thereby influences development and relapse of alcohol dependence. The dopamine D2 receptor (DRD2) gene on chromosome 11 (q22-q23) has been found to be associated with increased alcohol consumption through mechanisms involving incentive salience attributions and craving in alcoholic patients. Therefore, we investigated the association of three single nucleotide polymorphisms (SNP) in DRD2 gene with alcohol dependence in the north Indian subjects. Methods In a retrospective analysis, genetic association of three polymorphisms from DRD2 gene with alcohol dependence was investigated using a case-control approach. Alcohol dependence was determined by DSM-IV criteria and a total of 90 alcoholics and 60 healthy unrelated age-matched control subjects were recruited. Odds ratio and confidence interval was calculated to determine risk conferred by a predisposing allele/genotype/haplotype. Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair-wise interactions between SNPs. Results The study showed a significant association of -141C Ins allele and a trend of association of TaqI A1 allele of DRD2 with alcohol dependence. Haplotype with the predisposing -141C Ins and TaqI A1 alleles (-141C Ins-A-A1) seems to confer ≈ 2.5 times more risk to develop alcohol dependence. Conclusions The study provides preliminary insight into genetic risk to alcohol dependence in Indian males. Two polymorphisms namely, -141C Ins/Del and TaqI A in DRD2 gene may have clinical implications among Indian alcoholic subjects.
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Affiliation(s)
- Pushplata Prasad
- National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India
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Polymorphisms of alcohol metabolizing enzyme and cytochrome P4502E1 genes in mongolian population. Genes Genomics 2009. [DOI: 10.1007/bf03191256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Du Y, Wan YJY. The interaction of reward genes with environmental factors in contribution to alcoholism in mexican americans. Alcohol Clin Exp Res 2009; 33:2103-12. [PMID: 19764934 DOI: 10.1111/j.1530-0277.2009.01050.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Alcoholism is a polygenic disorder resulting from reward deficiency; polymorphisms in reward genes including serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR), A118G in opioid receptor mu1 (OPRM1), and -141C Insertion/Deletion (Ins/Del) in dopamine receptor D2 (DRD2) as well as environmental factors (education and marital status) might affect the risk of alcoholism. Objective of the current study was to examine the main and interacting effect of these 3 polymorphisms and 2 environmental factors in contribution to alcoholism in Mexican Americans. METHODS Genotyping of 5-HTTLPR, OPRM1 A118G, and DRD2-141C Ins/Del was performed in 365 alcoholics and 338 nonalcoholic controls of Mexican Americans who were gender- and age-matched. Alcoholics were stratified according to tertiles of MAXDRINKS, which denotes the largest number of drinks consumed in one 24-hour period. Data analysis was done in the entire data set and in each alcoholic stratum. Multinomial logistic regression was conducted to explore the main effect of 3 polymorphisms and 2 environmental factors (education and marital status); classification tree, generalized multifactor dimensionality reduction (GMDR) analysis, and polymorphism interaction analysis version 2.0 (PIA 2) program were used to study factor interaction. RESULTS Main effect of education, OPRM1, and DRD2 was detected in alcoholic stratum of moderate and/or largest MAXDRINKS with education < or =12 years, OPRM1 118 A/A, and DRD2 -141C Ins/Ins being risk factors. Classification tree analysis, GMDR analysis, and PIA 2 program all supported education*OPRM1 interaction in alcoholics of largest MAXDRINKS with education < or =12 years coupled with OPRM1 A/A being a high risk factor; dendrogram showed synergistic interaction between these 2 factors; dosage-effect response was also observed for education*OPRM1 interaction. No definite effect of marital status and 5-HTTLPR in pathogenesis of alcoholism was observed. CONCLUSIONS Our results suggest main effect of education background, OPRM1 A118G, and DRD2 -141C Ins/Del as well as education*OPRM1 interaction in contribution to moderate and/or severe alcoholism in Mexican Americans. Functional relevance of these findings still needs to be explored.
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Affiliation(s)
- Yanlei Du
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, U.S.A
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Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function. Pharmacogenet Genomics 2009; 19:513-27. [PMID: 19603545 DOI: 10.1097/fpc.0b013e32832d7fd3] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES The dopamine D2 receptor (DRD2) plays an important role in the reinforcing and motivating effects of ethanol. Several polymorphisms have been reported to affect receptor expression. The amount of DRD2, expressed in a given individual, is the result of the expression of both alleles, each representing a distinct haplotype. We examined the hypothesis that haplotypes composed of polymorphisms, associated with reduced receptor expression, are more frequent in alcoholics compared with healthy individuals. METHODS The polymorphisms -141ins/del, C957T, A1385G, and TaqlA were genotyped in a case-control sample comprising 360 alcoholics and 368 controls, and in a family-based sample of 65 trios. To investigate more homogenous groups, we constructed two subgroups with respect to age at onset and antisocial personality disorder. In addition, a subgroup with positive family history of alcoholism was investigated. RESULTS The haplotypes I-C-G-A2 and I-C-A-A1 occurred with a higher frequency in alcoholics [P=0.026, odds ratio (OR): 1.340; P=0.010, OR: 1.521, respectively]. The rare haplotype I-C-A-A2 occurred less often in alcoholics (P=0.010, OR: 0.507), and was also less often transmitted from parents to their affected offspring (1 vs.7). Among the subgroups, I-C-G-A2 and I-C-A-A1 had a higher frequency in Cloninger 1 alcoholics (P=0.083 and 0.001, OR: 1.917, respectively) and in alcoholics with a positive family history (P=0.031, OR: 1.478; P=0.073, respectively). Cloninger 2 alcoholics had a higher frequency of the rare haplotype D-T-A-A2 (P<0.001, OR: 4.614) always compared with controls. In patients with positive family history haplotype I-C-A-A2 (P=0.004, OR: 0.209), and in Cloninger 1 alcoholics haplotype I-T-A-A1 (P=0.045 OR: 0.460) were less often present. CONCLUSION We confirmed the hypothesis that haplotypes, which are supposed to induce a low DRD2 expression, are associated with alcohol dependence. Furthermore, supposedly high-expressing haplotypes weakened or neutralized the action of low-expressing haplotypes.
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Saiz PA, Garcia-Portilla MP, Florez G, Arango C, Corcoran P, Morales B, Bascaran MT, Alvarez C, San Narciso G, Carreño E, Alvarez V, Coto E, Bobes J. Differential role of serotonergic polymorphisms in alcohol and heroin dependence. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:695-700. [PMID: 19328219 DOI: 10.1016/j.pnpbp.2009.03.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Revised: 02/23/2009] [Accepted: 03/17/2009] [Indexed: 11/26/2022]
Abstract
BACKGROUND Twin studies suggest that genetic factors account for 40-60% of the variance in alcohol dependence. It has been stated that different drug dependencies may have unique genetic influences. Alterations in serotonin availability and function can affect drinking behaviour. This study aimed to investigate whether three serotonergic polymorphisms (HTR2A A-1438G (rs6311), and SCL6A4 5-HTTLPR and STin2 VNTR) were associated with alcohol dependence, and, whether the serotonergic polymorphisms played a similar role in conferring vulnerability in alcohol and heroin dependence. METHODS 165 alcohol dependent patients, 113 heroin dependent patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS Genotypic frequencies of the A-1438G, 5-HTTLPR, and STin2 VNTR polymorphisms did not differ significantly across the three groups. None of the three polymorphisms contributed to distinguishing alcoholic patients from healthy controls. There was an excess of -1438G and 5-HTTLPR L carriers in alcoholic patients in comparison to the heroin dependent group (OR (95% CI)=1.98 (1.13-3.45) and 1.92 (1.07-3.44), respectively). The A-1438G and 5-HTTLPR polymorphisms also interacted in distinguishing alcohol from heroin dependent patients (Wald (df)=10.21 (4), p=0.037). The association of -1438A/G with alcohol dependence was especially pronounced in the presence of 5-HTTLPR S/S, less evident with 5-HTTLPR L/S and not present with 5-HTTLPR L/L. SCL6A4 polymorphism haplotypes were similarly distributed in all three groups. CONCLUSIONS Our data do not support a role of serotonergic polymorphisms in alcohol dependence but suggest a differential genetic background to alcohol and heroin dependence.
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Affiliation(s)
- Pilar A Saiz
- Department of Psychiatry, School of Medicine, University of Oviedo, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Julian Claveria 6, 33006, Oviedo, Spain.
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Abstract
Alcohol dependence is a complex disorder which is influenced by physiological, psychological, environmental factors, individual inheritance and so on. Several candidate genes associated with alcohol dependence risk have been identified. The review focuses on several related genes that control alcohol metabolism such as alcohol dehydrogenase, aldehyde dehydrogenase, cytochrome P450 2E1 and regulate neurotransmission such as catechol-O-methyltransferase, dopamine receptors D2 and D4, and mu opioid receptor.
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Yang M, Tsuang J, Wan YJY. A haplotype analysis of CYP2E1 polymorphisms in relation to alcoholic phenotypes in Mexican Americans. Alcohol Clin Exp Res 2008; 31:1991-2000. [PMID: 18034693 DOI: 10.1111/j.1530-0277.2007.00533.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Studies regarding the association between the 4 polymorphisms of CYP2E1 (CYP2E1*1D, *5B, *6, and *1B) and alcoholism are inconsistent and inconclusive. The purpose of the present study was to clarify previously discordant studies by haplotype analysis in the Mexican American population. METHODS The 4 polymorphisms of CYP2E1 were studied in 334 alcoholics and 365 controls. Genotype, allele, and haplotype frequency comparisons between alcoholics and controls were assessed. Patterns of linkage disequilibrium (LD) at CYP2E1 were determined. Reconstructed haplotypes were tested for associations with clinical phenotypes (age onset of drinking, Maxdrinks, and smoking status). RESULTS No significant associations between the 4 polymorphisms of CYP2E1 and alcoholism were revealed by single allele tests. High LD was found between the CYP2E1 c2 and C alleles in Mexican Americans. Eleven haplotypes were present in the 699 participants. The 6 main haplotypes with frequencies higher than 1% made up 97% of the total halpotypes. The frequency of subjects carrying H6 (1C-c2-C-A2) was significantly higher in alcoholics than in controls (p = 0.0001). In contrast, the frequencies of H7 (1C-c2-C-A1) and H10 (1C-c2-D-A1) were significantly lower in alcoholics than in controls (p = 0.0072 for H7 and p = 0.0407 for H10). The frequency of H6 was significantly higher in alcoholics who had late onset of drinking than in nonalcoholic controls. Furthermore, the frequencies of H6 haplotype were also consistently higher in groups who had high number of maximum drinks (9 to 32 drinks) than in controls. When smokers are excluded, the frequencies of H6, H7, and H9 (1C-c2-D-A2) showed statistically significant differences between alcoholics and controls (p < 0.05). Moreover, the association between H6 and alcoholism become more robust when smokers are excluded. Furthermore, the frequency of H1 (1C-c1-D-A2) in alcoholic-smokers was much higher than in alcoholic-nonsmokers (p = 0.0028). In contrast, alcoholic-smokers carried less H2 (1C-c1-D-A1) in comparison with alcoholic-nonsmokers (p = 0.0417). The H3 (1D-c2-C-A2) frequency in alcoholic-smokers was much lower than in alcoholic-nonsmokers (p = 0.0042) and control-smokers (p = 0.0363). CONCLUSIONS Our data demonstrate that carrying haplotype H6 might enhance susceptibility to developing alcoholism, but possessing the H7 or H10 haplotype appears to decrease this susceptibility. The H6, H7, and H9 haplotypes may play certain roles in different clinical phenotypes in Mexican American alcoholics. In addition, our data suggest that the H1, H2, and H3 haplotypes are associated with alcohol drinking and smoking. These results support that haplotype analysis is much more informative than single allele analysis. Our findings clearly indicate the importance of H6 haplotype in alcohol drinking in Mexican Americans.
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Affiliation(s)
- Min Yang
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
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Smith L, Watson M, Gates S, Ball D, Foxcroft D. Meta-analysis of the association of the Taq1A polymorphism with the risk of alcohol dependency: a HuGE gene-disease association review. Am J Epidemiol 2008; 167:125-38. [PMID: 17989061 DOI: 10.1093/aje/kwm281] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The human dopamine 2 receptor Taq1A allele has been implicated as a vulnerability factor for alcohol dependence in a number of studies and reviews. To determine whether this allele is associated with alcoholism, the authors conducted a Human Genome Epidemiology review and meta-analysis. Forty-four studies with 9,382 participants were included. An odds ratio of 1.38 (95% confidence interval: 1.20, 1.58; heterogeneity, 50.5%) was found for the A1A1 + A1A2 versus the A2A2 genotype. Sensitivity analyses suggested lack of ethnic matching as a possible source of heterogeneity; a small, significant association was detected in studies with ethnic-matched controls (odds ratio = 1.26, 95% confidence interval: 1.02, 1.56; heterogeneity, 37%). Significant associations were also found in analyses restricted to studies reporting use of blinding and those with adequate screening of controls for alcohol dependency. For the A1A1 versus the A1A2 + A2A2 genotype, the odds ratio was 1.22 (95% confidence interval: 1.05, 1.43; heterogeneity, 0%). Sensitivity analyses on groups of studies reporting use of ethnic-matched controls and those that screened controls for alcohol dependency still showed significant associations. The relatively small effect for the association of the A1 allele, or another genetic variant linked to it, with alcohol dependence indicates a multigene causality for this complex disorder.
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Affiliation(s)
- Lesley Smith
- School of Health and Social Care, Oxford Brookes University, Marston, United Kingdom.
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Tolstrup JS, Nordestgaard BG, Rasmussen S, Tybjaerg-Hansen A, Grønbaek M. Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes. THE PHARMACOGENOMICS JOURNAL 2007; 8:220-7. [PMID: 17923853 DOI: 10.1038/sj.tpj.6500471] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcohol drinking habits and alcoholism are partly genetically determined. Alcohol is degraded primarily by alcohol dehydrogenase (ADH) wherein genetic variation that affects the rate of alcohol degradation is found in ADH1B and ADH1C. It is biologically plausible that these variations may be associated with alcohol drinking habits and alcoholism. By genotyping 9080 white men and women from the general population, we found that men and women with ADH1B slow vs fast alcohol degradation drank more alcohol and had a higher risk of everyday drinking, heavy drinking, excessive drinking and of alcoholism. For example, the weekly alcohol intake was 9.8 drinks (95% confidence interval (CI): 9.1-11) among men with the ADH1B.1/1 genotype compared to 7.5 drinks (95% CI: 6.4-8.7) among men with the ADH1B.1/2 genotype, and the odds ratio (OR) for heavy drinking was 3.1 (95% CI: 1.7-5.7) among men with the ADH1B.1/1 genotype compared to men with the ADH1B.1/2 genotype. Furthermore, individuals with ADH1C slow vs fast alcohol degradation had a higher risk of heavy and excessive drinking. For example, the OR for heavy drinking was 1.4 (95% CI: 1.1-1.8) among men with the ADH1C.1/2 genotype and 1.4 (95% CI: 1.0-1.9) among men with the ADH1B.2/2 genotype, compared with men with the ADH1C.1/1 genotype. Results for ADH1B and ADH1C genotypes among men and women were similar. Finally, because slow ADH1B alcohol degradation is found in more than 90% of the white population compared to less than 10% of East Asians, the population attributable risk of heavy drinking and alcoholism by ADH1B.1/1 genotype was 67 and 62% among the white population compared with 9 and 24% among the East Asian population.
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Green RF, Stoler JM. Alcohol dehydrogenase 1B genotype and fetal alcohol syndrome: a HuGE minireview. Am J Obstet Gynecol 2007; 197:12-25. [PMID: 17618743 DOI: 10.1016/j.ajog.2007.02.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2006] [Revised: 02/16/2007] [Accepted: 02/22/2007] [Indexed: 12/20/2022]
Abstract
Fetal alcohol syndrome (FAS), 1 of the most common developmental disabilities in the United States, occurs at a rate of 0.5-2.0:1000 live births. Animal model, family, and twin studies suggest a genetic component to FAS susceptibility. Alcohol dehydrogenases (ADHs) catalyze the rate-limiting step in alcohol metabolism. Studies of genetic associations with FAS have focused on the alcohol dehydrogenase 1B (ADH1B) gene, comparing mothers and children with the alleles ADH1B*2 or ADH1B*3, associated with faster ethanol metabolism, with those homozygous for ADH1B*1. While most studies have found a protective effect for genotypes containing ADH1B*2 or ADH1B*3, results have been conflicting, and further investigation into the association between the ADH1B genotype and FAS is needed. Whether increased alcohol intake accounts for the elevated risk reported for the ADH1B*1/ADH1B*1 genotype should be addressed, and future studies would benefit from consistent case definitions, enhanced exposure measurements, larger sample sizes, and careful study design.
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Affiliation(s)
- Ridgely Fisk Green
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Sakai JT, Hopfer CJ, Hartman C, Haberstick BC, Smolen A, Corley RP, Stallings MC, Young SE, Timberlake D, Hewitt JK, Crowley TJ. Test of association between TaqIA A1 allele and alcohol use disorder phenotypes in a sample of adolescent patients with serious substance and behavioral problems. Drug Alcohol Depend 2007; 88:130-7. [PMID: 17069991 DOI: 10.1016/j.drugalcdep.2006.10.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2006] [Revised: 10/02/2006] [Accepted: 10/03/2006] [Indexed: 11/20/2022]
Abstract
UNLABELLED Several studies have demonstrated a significant association between the A1 allele of the TaqIA polymorphism and various phenotypes of alcoholism, others have not, and two studies have shown the reversed association, where the A2 allele was associated with higher levels of alcohol consumption. We sought to test for an association between early onset (in childhood or adolescence) alcohol use disorders and the DRD2 TaqIA polymorphism and to resolve some of the hypothesized explanations for previous negative results, utilizing a larger sample than many previous studies. METHODS We selected individuals with a lifetime alcohol abuse or dependence (n=239) diagnosis from a clinically ascertained sample of youth (ages 13-19) with serious conduct and substance problems (about 90% also met criteria for conduct disorder and a cannabis use disorder) and compared them with individuals without a lifetime alcohol use disorder diagnosis ascertained from (1) community adolescent controls (n=151), (2) siblings of patients (n=87) and (3) other adolescent patients (n=92). Cases were compared with each control group, separately, by genotype using the chi(2)-test. Using 78 adolescent patients with an alcohol use disorder where genotypic information was available for both parents, we conducted the transmission disequilibrium test (TDT). RESULTS Case-control results were non-significant using the entire community control sample (chi(2)(2)=1.92; p=0.38) and when restricting the sample to Caucasians (chi(2)(2)=3.81; p=0.15) or Hispanics (chi(2)(2)=1.70; p=0.43). Case-control results using the other comparison groups and TDT results were also non-significant. DISCUSSION We did not find support for an association between the TaqIA polymorphism and early onset alcohol use disorders.
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Affiliation(s)
- Joseph T Sakai
- Department of Psychiatry, Division of Substance Dependence, University of Colorado School of Medicine, Denver, CO 80262, USA.
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Dick DM, Plunkett J, Hamlin D, Nurnberger J, Kuperman S, Schuckit M, Hesselbrock V, Edenberg H, Bierut L. Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Psychiatr Genet 2007; 17:35-8. [PMID: 17167343 DOI: 10.1097/ypg.0b013e328011188b] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The objective of this study was to analyze association of the serotonin transporter gene 5-HTTLPR polymorphism on lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. We conducted family-based association analyses in 1913 Caucasians genotyped for the 5-HTTLPR polymorphism. We found evidence for association of the short allele with depression, but no evidence of association with alcohol dependence. On the basis of the evidence that the effect of this polymorphism may be moderated by stressful life events, we classified individuals for the presence and/or absence of stress, as defined by unemployment, relationship problems, or poor health. The evidence for the association with lifetime depression was limited to the group of individuals who had experienced stress, paralleling the direction of effects originally reported by Caspi and colleagues. No evidence was found for the association with alcohol dependence in either the stress or the no-stress groups.
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Affiliation(s)
- Danielle M Dick
- Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri 63110, USA.
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Lott DC, Kim SJ, Cook EH, de Wit H. Serotonin transporter genotype and acute subjective response to amphetamine. Am J Addict 2007; 15:327-35. [PMID: 16966188 DOI: 10.1080/10550490600859868] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
The authors have previously shown an effect of dopamine transporter genotype on acute subjective responses to d-amphetamine, which may affect risk of addiction. They now report the results of an evaluation of the role of the serotonin transporter gene (HTT) using a double-blind, placebo-controlled, crossover design in which subjects (N = 101) completed self-report measures of subjective effect. The separate and combined analyses of the gene-linked polymorphic region (5-HTTLPR) and the Intron 2 VNTR suggest that these two HTT polymorphisms may contribute to acute subjective responses to d-amphetamine with a small effect.
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Affiliation(s)
- David C Lott
- Linden Oaks Hospital at Edward, Naperville, Illinois, USA.
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Samochowiec J, Kucharska-Mazur J, Grzywacz A, Jabłoński M, Rommelspacher H, Samochowiec A, Sznabowicz M, Horodnicki J, Sagan L, Pełka-Wysiecka J. Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence. Neurosci Lett 2006; 410:1-5. [DOI: 10.1016/j.neulet.2006.05.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2006] [Revised: 04/29/2006] [Accepted: 05/02/2006] [Indexed: 11/16/2022]
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Gene-alcohol interactions in the metabolic syndrome. Nutr Metab Cardiovasc Dis 2006; 17:140-7. [PMID: 17008075 DOI: 10.1016/j.numecd.2006.02.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2006] [Revised: 02/03/2006] [Accepted: 02/20/2006] [Indexed: 12/17/2022]
Abstract
AIMS Recent studies have reported that moderate alcohol consumption is associated with a lesser prevalence of the metabolic syndrome (MetS). However, this relationship is still confusing and the presence of gene-environment interactions has been suggested. Our aim is to summarize evidence for gene-alcohol interactions in the MetS. DATA SYNTHESIS Research in gene-alcohol interactions applied to MetS is very complex due to the difficulties surrounding the definition of phenotype, environment and genotype, as well as in estimating the influence of the social context. In the MetS there is a constellation of metabolic disturbances the definition of which is still changing. Thus, most studies that have reported on gene-alcohol interactions have done so by analyzing isolated components. Likewise, the definition of alcohol consumption is also complex given that apart from the amount of ethanol consumed, the type of drink, the frequency of consumption, etc., may be important. No less difficult is the definition of genotype as there are many candidate genes involved, including not only those relevant for each phenotype studied, but also those related with alcohol metabolism, as well as those related to alcohol intake. CONCLUSIONS Although various studies exist that show statistically significant interactions between alcohol consumption and MetS components, a greater integration of variables as well as greater homogeneity in definitions is required.
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Trujillo KA, Castañeda E, Martínez D, González G. Biological research on drug abuse and addiction in Hispanics: current status and future directions. Drug Alcohol Depend 2006; 84 Suppl 1:S17-28. [PMID: 16777354 DOI: 10.1016/j.drugalcdep.2006.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Impressive progress has been made in the understanding of biological contributions to drug abuse and addiction. An area that has only recently begun to receive attention is potential ethnic and racial differences in biological systems that contribute to, or protect from, problem drug use. This article reviews recent research on drug abuse and addiction in Hispanics in which biological questions have been addressed, including work on genes, gene products (proteins), physiology and pharmacotherapy. Taken together, work to date suggests that there are both similarities and differences between Hispanics and other ethnic groups in biological factors related to drug abuse and addiction. Although the results are intriguing, relatively few studies have been done, and those that have been done have often been inconclusive due to low numbers of Hispanic subjects. Moreover, studies have often failed to recognize the complexity and heterogeneity of Hispanic populations in the United States and around the world. After reviewing the current status of the field, recommendations are given for future research in both humans and relevant animal models that will lead to a better understanding of drug abuse and addiction in Hispanics.
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Affiliation(s)
- Keith A Trujillo
- Department of Psychology and Office for Biomedical Research and Training, California State University San Marcos, San Marcos, CA 92096, USA.
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