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Al-Eitan L, Mihyar A, Alghamdi M. Assessing the association between ADH5 and ALDH1A1 genetic variants and substance use disorder risk in a Jordanian male population. BMC Genomics 2025; 26:210. [PMID: 40033181 PMCID: PMC11874114 DOI: 10.1186/s12864-025-11379-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 02/18/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Substance Use Disorder (SUD) is a severe global problem that is influenced by both environmental and genetic factors. The genetic etiology of addiction can be complex and overlapping. This study aimed to investigate the association between two genes, ADH5 and ALDH1A1, and drug addiction in Jordanian males. METHODS This study included 496 addicted patients and 496 healthy controls of Arab descent. The addicted participants were identified as Jordanian males with dependence on substances such as amphetamines, synthetic cannabinoids, benzodiazepines, alcohol, opiates, cocaine, and multiple substances. The participants' DNA was extracted, and 20 selected SNPs within ADH5 and ALDH1A1 were genotyped using the MassARRAY™ system. The statistical analysis was carried out using SPSS. RESULTS The study investigated associations between 20 variants within the ADH5 and ALDH1A1 genes and substance use disorder in Jordanian males. No statistically significant association was observed between individual polymorphisms and addiction (P > 0.05). However, the haplotypes CCGTTTTGTTTGG and CCCTTGTGTTCGG within the ALDH1A1 gene were significantly associated with an increased risk of addiction, with P-values of 0.0022 and 0.049 and odds ratios (OR) of 2.34 and 1.91, respectively. CONCLUSION This study did not find a significant association between ADH5 and ALDH1A1 gene polymorphisms with addiction in Jordanian males. The authors suggest replicating this type of study with larger sample sizes and more variants in the same or different genes to confirm their findings.
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Affiliation(s)
- Laith Al-Eitan
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, 22110, Jordan.
| | - Ahmad Mihyar
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, 22110, Jordan
| | - Mansour Alghamdi
- Department of Anatomy, College of Medicine, King Khalid University, 62529, Abha, Saudi Arabia
- Genomics and Personalized Medicine Unit, The Center for Medical and Health Research, King Khalid University, 62529, Abha, Saudi Arabia
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Wang L, Kranzler HR, Gelernter J, Zhou H. Investigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries. Biol Psychiatry 2025:S0006-3223(25)00062-9. [PMID: 39892688 DOI: 10.1016/j.biopsych.2025.01.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 12/16/2024] [Accepted: 01/26/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants that underlie AUD. However, whole-exome sequencing studies of AUD have been hampered by the lack of available samples. METHODS We analyzed whole-exome sequencing data of 4530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank, which represent an unprecedented resource for exploring the contribution of coding variants in AUD. After quality control, 1750 African-ancestry (1142 cases) and 2039 European-ancestry (1420 cases) samples from the Yale-Penn and 6142 African-ancestry (130 cases), 415,617 European-ancestry (12,861 cases), and 4607 South Asian (130 cases) samples from the UK Biobank cohorts were included in the analyses. RESULTS We confirmed the well-known functional variant rs1229984 in ADH1B (p = 4.88 × 10-31) and several other variants in ADH1C. Gene-based collapsing tests that considered the high allelic heterogeneity revealed the previously unreported genes CNST (p = 1.19 × 10-6), attributable to rare variants with allele frequency < 0.001, and IFIT5 (p = 3.74 × 10-6), driven by the burden of both common and rare loss-of-function and missense variants. CONCLUSIONS This study extends our understanding of the genetic architecture of AUD by providing insights into the contribution of rare coding variants, separately and convergently with common variants in AUD.
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Affiliation(s)
- Lu Wang
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Henry R Kranzler
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania
| | - Joel Gelernter
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut; Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut.
| | - Hang Zhou
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, Connecticut; Center for Brain and Mind Health, Yale School of Medicine, New Haven, Connecticut.
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Xia N, Xue H, Li Y, Liu J, Lou Y, Li S, Wang Y, Lu J, Chen X. Potential Mechanisms and Effects of Dai Bai Jie Ethanol Extract in Preventing Acute Alcoholic Liver Injury. Curr Issues Mol Biol 2024; 47:3. [PMID: 39852118 PMCID: PMC11763393 DOI: 10.3390/cimb47010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/26/2025] Open
Abstract
This study investigated the protective effect of Dai Bai Jie (DBJ) extract against acute alcoholic liver injury (AALI) and elucidated its potential mechanism. The total saponin level in the DBJ extracts was measured using vanillin-chloroform acid colorimetry. To observe the preventive and protective effects of DBJ on AML-12 cells in an ethanol environment, the effective components of DBJ were identified. An alcohol-induced AALI mouse model was used to evaluate the efficacy of DBJ against AALI. For this purpose, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) levels were assessed, liver function indices and oxidative and inflammatory markers were determined, and histopathological examinations were performed. Mechanistic investigations were conducted using RT-qPCR assays and immunohistochemical analysis to determine the protective effects of DBJ. The samples (DBJ-1, DBJ-2, and DBJ-3) were obtained by extracting DBJ with water, 50% ethanol, and 95% ethanol, yielding total saponin contents of 5.35%, 6.64%, and 11.83%, respectively. DBJ-3 was isolated and purified, and its components were identified by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). DBJ-3 had the greatest effect on cell viability in an ethanol environment. Moreover, DBJ-3 reduced inflammatory infiltration, liver cell degeneration, and hemorrhage, while increasing ADH and ALDH levels in liver tissues. Additionally, DBJ-3 considerably decreased the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglyceride (TG) levels. DBJ-3 reduced malondialdehyde (MDA), reactive oxygen species (ROS), and inflammatory factors, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), while increasing superoxide dismutase (SOD) and glutathione S-transferase (GST) activities. Furthermore, DBJ-3 significantly increased alcohol dehydrogenase 1b (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) expression at the gene and protein levels within alcohol metabolism pathways and reduced the nuclear factor kappa-B (NF-κB) gene and protein levels. These findings suggest that DBJ-3 can prevent AALI by enhancing alcohol metabolism via the regulation of ADH1B and ALDH2 and the modulation of the NF-κB pathway to improve antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Niantong Xia
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Hongwei Xue
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yihang Li
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong 666100, China;
| | - Jia Liu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yang Lou
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Shuyang Li
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yutian Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Juan Lu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Xi Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong 666100, China;
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Adasme-Reyes S, Fuentes J, Gutiérrez-Vega I, Isla E, Pérez V, Ponce C, Quilaqueo ME, Herrera-Marschitz M, Quintanilla ME, Vásquez D, Rivera-Meza M. Pharmacological activators of ALDH2: A new strategy for the treatment of alcohol use disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 178:153-177. [PMID: 39523053 DOI: 10.1016/bs.irn.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
In mammals, ethanol is metabolized to acetaldehyde mainly by the liver alcohol dehydrogenase (ADH), and acetaldehyde is subsequently oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). The presence of an inactive variant of ALDH2 or the use of inhibitors of this enzyme leads to an accumulation of acetaldehyde after ethanol consumption, generating an aversive reaction that inhibits subsequent alcohol intake. However, experimental evidence shows that acetaldehyde has potent rewarding effects at the central level, suggesting that acetaldehyde would be responsible for the addictive effect of alcohol. Alda-1 is an organic molecule that acts as a pharmacological activator of ALDH2. Studies in animal models of alcohol use disorders (AUD; i.e. alcoholism) have shown that Alda-1 can inhibit the acquisition, the chronic intake, and the relapse of alcohol consumption. These effects are reversible without any effects on water consumption or other natural reinforcer such as saccharin. It has also been reported that Alda-1 can act as a protective agent from the toxic effects on various tissues and organs mediated by ethanol-derived acetaldehyde, including liver damage, cancer, and central nervous system (CNS) alterations. Using in silico tools such as molecular docking the identification of important molecular interactions between Alda-1 and ALDH2 has been demonstrated, identifying new molecules with higher pharmacological features. Thus, there is now preclinical evidence supporting the use of activators of ALDH2 as a pharmacological strategy for the treatment of AUD.
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Affiliation(s)
- Sofía Adasme-Reyes
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Juan Fuentes
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Ignacio Gutiérrez-Vega
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Eduardo Isla
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Vicente Pérez
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Carolina Ponce
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - María Elena Quilaqueo
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Mario Herrera-Marschitz
- Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Santiago, Chile
| | - María Elena Quintanilla
- Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Santiago, Chile
| | - David Vásquez
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile
| | - Mario Rivera-Meza
- Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile, Santiago, Chile.
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Zhou H, Gelernter J. Human genetics and epigenetics of alcohol use disorder. J Clin Invest 2024; 134:e172885. [PMID: 39145449 PMCID: PMC11324314 DOI: 10.1172/jci172885] [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: 08/16/2024] Open
Abstract
Alcohol use disorder (AUD) is a prominent contributor to global morbidity and mortality. Its complex etiology involves genetics, epigenetics, and environmental factors. We review progress in understanding the genetics and epigenetics of AUD, summarizing the key findings. Advancements in technology over the decades have elevated research from early candidate gene studies to present-day genome-wide scans, unveiling numerous genetic and epigenetic risk factors for AUD. The latest GWAS on more than one million participants identified more than 100 genetic variants, and the largest epigenome-wide association studies (EWAS) in blood and brain samples have revealed tissue-specific epigenetic changes. Downstream analyses revealed enriched pathways, genetic correlations with other traits, transcriptome-wide association in brain tissues, and drug-gene interactions for AUD. We also discuss limitations and future directions, including increasing the power of GWAS and EWAS studies as well as expanding the diversity of populations included in these analyses. Larger samples, novel technologies, and analytic approaches are essential; these include whole-genome sequencing, multiomics, single-cell sequencing, spatial transcriptomics, deep-learning prediction of variant function, and integrated methods for disease risk prediction.
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Affiliation(s)
- Hang Zhou
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
- Department of Biomedical Informatics and Data Science
- Center for Brain and Mind Health
| | - Joel Gelernter
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
- Department of Genetics, and
- Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA
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Huang A, Zou C, Dai Z, Sun Y, Wang J, Liu S, Han L, Chen S, Liang Q, Wang C, Zhuang Y, Dang T, Chang B, Wang Y, Zou Z. Mild-moderate alcohol consumption and diabetes are associated with liver fibrosis in patients with biopsy-proven MASLD. Front Pharmacol 2024; 15:1437479. [PMID: 39144624 PMCID: PMC11322122 DOI: 10.3389/fphar.2024.1437479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/17/2024] [Indexed: 08/16/2024] Open
Abstract
Background It is unclear whether patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are allowed variable low levels of alcohol. This study aimed to evaluate the effect of mild-moderate alcohol consumption on the biochemical and histological characteristics of patients with MASLD. Methods Alcohol consumption was assessed in 713 patients with steatotic liver disease (SLD) who underwent liver biopsy. Non-drinking, mild-moderate drinking, and excessive drinking were defined as 0 g/day, 1-<20 g/day, and >20 g/day for women and 0 g/day, 1-<30 g/day, and >30 g/day for men, respectively. Liver biopsies were scored according to the NASH CRN system. Results A total of 713 participants (median age 39.0 years and 77.1% male) with biopsy-proven SLD were enrolled, including 239 nondrinkers, 269 mild-moderate drinkers and 205 excessive drinkers. Excessive drinking was associated with increased risks for lobular inflammation and liver fibrosis compared to nondrinkers and mild-moderate drinkers. Compared with non-drinkers, mild-moderate drinkers had significantly lower odds for steatosis (OR = 0.60, 95% CI = 0.38-0.93, p = 0.025), hepatocellular ballooning (OR = 0.52, 95% CI = 0.29-0.91, p = 0.020) and fibrosis (OR = 0.50, 95% CI = 0.31-0.81, p = 0.005). However, in non-excessive drinkers with type 2 diabetes mellitus (T2DM), there was no association between mild-moderate alcohol consumption and liver fibrosis (OR = 0.562, 95% CI = 0.207-1.530, p = 0.257). Conclusions Mild-moderate alcohol consumption might be protective against liver fibrosis in MASLD patients, which is modified by the presence of T2DM. However, further longitudinal studies are needed to determine the effect of ongoing alcohol consumption on disease severity.
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Affiliation(s)
- Ang Huang
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Gastroenterology and Hepatology, The First Medical Center of PLA General Hospital, Beijing, China
| | - Cailun Zou
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Zhe Dai
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Ying Sun
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jing Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Shuhong Liu
- Department of Pathology and Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Lin Han
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Songhai Chen
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Qingsheng Liang
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Chunyan Wang
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yingjie Zhuang
- Department for Disease Control and Prevention, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tong Dang
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Binxia Chang
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yijin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Zhengsheng Zou
- Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
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Koyama E, Kant T, Takata A, Kennedy JL, Zai CC. Genetics of child aggression, a systematic review. Transl Psychiatry 2024; 14:252. [PMID: 38862490 PMCID: PMC11167064 DOI: 10.1038/s41398-024-02870-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 06/13/2024] Open
Abstract
Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.
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Affiliation(s)
- Emiko Koyama
- Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, Wako, Japan
| | - Tuana Kant
- Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Atsushi Takata
- Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, Wako, Japan
| | - James L Kennedy
- Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Clement C Zai
- Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Wang L, Kranzler HR, Gelernter J, Zhou H. Multi-ancestry Whole-exome Sequencing Study of Alcohol Use Disorder in Two Cohorts. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.04.05.24305412. [PMID: 38645055 PMCID: PMC11030482 DOI: 10.1101/2024.04.05.24305412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants underlying AUD. However, there are few whole-exome sequencing (WES) studies of AUD. We analyzed WES of 4,530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank (UKB). After quality control, 1,420 AUD cases and 619 controls of European ancestry (EUR) and 1,142 cases and 608 controls of African ancestry (AFR) from Yale-Penn were retained for subsequent analyses. WES data from 415,617 EUR samples (12,861 cases), 6,142 AFR samples (130 cases) and 4,607 South Asian (SAS) samples (130 cases) from UKB were also analyzed. Single-variant association analysis identified the well-known functional variant rs1229984 in ADH1B ( P =4.88×10 -31 ) and several other common variants in ADH1C . Gene-based tests identified ADH1B ( P =1.00×10 -31 ), ADH1C ( P =5.23×10 -7 ), CNST ( P =1.19×10 -6 ), and IFIT5 (3.74×10 -6 ). This study extends our understanding of the genetic basis of AUD.
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Hu M, Song JX, Miao ST, Wu CK, Gong XW, Sun HJ. Rational design of soluble expressed human aldehyde dehydrogenase 2 with high stability and activity in pepsin and trypsin. Int J Biol Macromol 2024; 265:131091. [PMID: 38521319 DOI: 10.1016/j.ijbiomac.2024.131091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 03/25/2024]
Abstract
Acetaldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme in alcohol metabolism, and oral administration of ALDH2 is a promising method for alcohol detoxification. However, recombinant ALDH2 is susceptible to hydrolysis by digestive enzymes in the gastrointestinal tract and is expressed as inactive inclusion bodies in E. coli. In this study, we performed three rounds of rational design to address these issues. Specifically, the surface digestive sites of pepsin and trypsin were replaced with other polar amino acids, while hydrophobic amino acids were incorporated to reshape the catalytic cavity of ALDH2. The resulting mutant DE2-852 exhibited a 45-fold increase in soluble expression levels, while its stability against trypsin and pepsin increased by eightfold and twofold, respectively. Its catalytic efficiency (kcat/Km) at pH 7.2 and 3.2 improved by more than four and five times, respectively, with increased Vmax and decreased Km values. The enhanced properties of DE2-852 were attributed to the D457Y mutation, which created a more compact protein structure and facilitated a faster collision between the substrate and catalytic residues. These results laid the foundation for the oral administration and mass preparation of highly active ALDH2 and offered insights into the oral application of other proteins.
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Affiliation(s)
- Min Hu
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China
| | - Jia-Xu Song
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China
| | - Shi-Tao Miao
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China
| | - Cheng-Kai Wu
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China
| | - Xing-Wen Gong
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Hong-Ju Sun
- School of Life Sciences, Inner Mongolia University, Hohhot 010020, China.
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Han MJ, Kim ST, Park CI, Hwang SS, Kim HW, Kang JI, Kim SJ. Serial mediating effects of childhood trauma and conduct behaviors on the impact of family history among patients with alcohol use disorder. Sci Rep 2024; 14:7196. [PMID: 38532019 DOI: 10.1038/s41598-024-57861-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/22/2024] [Indexed: 03/28/2024] Open
Abstract
Family history (FH) of alcoholism increases the risk of alcohol use disorder (AUD); however, the contribution of childhood trauma (CT) in this respect remains unclear. This study investigated the relationship between FH and AUD-related clinical characteristics (social onset, antisocial tendency, and severity of problematic alcohol consumption) through the mediating effects of childhood trauma (CT) and conduct behaviors (CB) in a Korean male population with AUD. A total of 304 patients hospitalized for AUD at 16 psychiatric hospitals completed standardized questionnaires, including self-rated scales. Mediation analyses were performed using the SPSS macro PROCESS. Individuals with positive FH (133, 44%) had greater CT and CB and more severe AUD-related clinical characteristics than those without FH (171, 56%). In the present serial mediation model, FH had significant direct and indirect effects on AUD-related clinical characteristics through CT and CB. Indirect effects were 21.3% for social onset, 46.3%, antisocial tendency, and 37.9% for problematic drinking. FH directly contributed to AUD-related clinical characteristics, and CT and CB played mediating roles. This highlights the importance of careful intervention and surveillance of adverse childhood experiences and conduct disorder to prevent and mitigate alcohol-related problems in individuals with FH of AUD.
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Affiliation(s)
- Min Jeong Han
- Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Shin Tae Kim
- Graduate School, Yonsei University College of Medicine, Seoul, South Korea
| | - Chun Il Park
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Syung Shick Hwang
- Graduate School, Yonsei University College of Medicine, Seoul, South Korea
| | - Hae Won Kim
- Department of Medical Education, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Jee In Kang
- Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea.
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea.
| | - Se Joo Kim
- Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea.
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea.
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11
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Cho Y, Lin K, Lee SH, Yu C, Valle DS, Avery D, Lv J, Jung K, Li L, Smith GD, China Kadoorie Biobank Collaborative Group, Sun D, Chen Z, Millwood IY, Hemani G, Walters RG. Genetic influences on alcohol flushing in East Asian populations. BMC Genomics 2023; 24:638. [PMID: 37875790 PMCID: PMC10594868 DOI: 10.1186/s12864-023-09721-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.
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Affiliation(s)
- Yoonsu Cho
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, UK
| | - Kuang Lin
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Su-Hyun Lee
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Canqing Yu
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, 100191, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, 100191, China
| | - Dan Schmidt Valle
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Daniel Avery
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Jun Lv
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, 100191, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, 100191, China
| | - Keumji Jung
- Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Liming Li
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, 100191, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, 100191, China
| | - George Davey Smith
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, UK
| | | | - Dianjianyi Sun
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, 100191, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, 100191, China
| | - Zhengming Chen
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- MRC Population Health Research Unit, University of Oxford, Oxford, UK
| | - Iona Y Millwood
- Nuffield Department of Population Health, University of Oxford, Oxford, UK.
- MRC Population Health Research Unit, University of Oxford, Oxford, UK.
| | - Gibran Hemani
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
- Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, UK.
| | - Robin G Walters
- Nuffield Department of Population Health, University of Oxford, Oxford, UK.
- MRC Population Health Research Unit, University of Oxford, Oxford, UK.
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12
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杨 群, 刘 晓, 蒋 玉, 马 进. [Aldehyde dehydrogenase 2 rs671 genetic polymorphisms are associated with chemotherapy-induced nausea and vomiting]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:1017-1022. [PMID: 37439175 PMCID: PMC10339303 DOI: 10.12122/j.issn.1673-4254.2023.06.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Indexed: 07/14/2023]
Abstract
OBJECTIVE To investigate the correlation between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and chemotherapy-induced nausea and vomiting (CINV). METHODS A total of 90 Chinese patients with malignant tumors receiving chemotherapy for the first time were recruited in this study. The occurrence of CINV was observed within 120 h after treatment with docetaxel and cis-platinum chemotherapy (DP regimen). The data of the patients (including age, gender, tumor stage, habitual alcohol consumption, motion sickness, morning sickness, and average sleep time prior to chemotherapy) were collected through a questionnaire. ALDH2 rs671 polymorphisms of the patients were analyzed using a multiple single nucleotide polymorphism genotyping, and the Hardy-Weinberg equation was used for genetic linkage analysis. The correlations between the factors including ALDH2 rs671 polymorphisms and the occurrence of CINV were analyzed. RESULTS The incidence of CINV was 48.9% among the patients receiving their first chemotherapy with DP regimen. Univariate analysis indicated that the genetic polymorphisms of ALDH2 rs671 were significantly correlated with the occurrence of CINV (P < 0.05). Multivariate logistic analysis indicated that ALDH2 rs671 mutation (OR: 3.019, 95% CI: 1.056-8.628, P < 0.05) and average sleep time prior to chemotherapy no longer than 6 h (OR: 2.807, 95% CI: 1.033-7.628, P < 0.05) were risk factors for CINV in patients with malignant tumors receiving the first chemotherapy with DP regimen. CONCLUSION ALDH2 gene mutation at rs671 is a risk factor contributing to the occurrence of CINV, and understanding of the underlying mechanism may help to more effectively control the occurrence of CINV.
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Affiliation(s)
- 群 杨
- 中南大学湘雅二医院临床护理教研室，湖南 长沙 410011Clinical Nursing Teaching and Research Section, Second Xiangya Hospital, Central South University, Changsha 410011, China
- 中南大学湘雅二医院肿瘤科，湖南 长沙 410011Department of Oncology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 晓鑫 刘
- 中南大学湘雅二医院临床护理教研室，湖南 长沙 410011Clinical Nursing Teaching and Research Section, Second Xiangya Hospital, Central South University, Changsha 410011, China
- 中南大学湘雅二医院肿瘤科，湖南 长沙 410011Department of Oncology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 玉娜 蒋
- 中南大学湘雅二医院肿瘤科，湖南 长沙 410011Department of Oncology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 进安 马
- 中南大学湘雅二医院肿瘤科，湖南 长沙 410011Department of Oncology, Second Xiangya Hospital, Central South University, Changsha 410011, China
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Xia J, Li S, Liu S, Zhang L. Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets. MedComm (Beijing) 2023; 4:e195. [PMID: 36694633 PMCID: PMC9842923 DOI: 10.1002/mco2.195] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 01/18/2023] Open
Abstract
The family of aldehyde dehydrogenases (ALDHs) contains 19 isozymes and is involved in the oxidation of endogenous and exogenous aldehydes to carboxylic acids, which contributes to cellular and tissue homeostasis. ALDHs play essential parts in detoxification, biosynthesis, and antioxidants, which are of important value for cell proliferation, differentiation, and survival in normal body tissues. However, ALDHs are frequently dysregulated and associated with various diseases like Alzheimer's disease, Parkinson's disease, and especially solid tumors. Notably, the involvement of the ALDHs in tumor progression is responsible for the maintenance of the stem-cell-like phenotype, triggering rapid and aggressive clinical progressions. ALDHs have captured increasing attention as biomarkers for disease diagnosis and prognosis. Nevertheless, these require further longitudinal clinical studies in large populations for broad application. This review summarizes our current knowledge regarding ALDHs as potential biomarkers in tumors and several non-tumor diseases, as well as recent advances in our understanding of the functions and underlying molecular mechanisms of ALDHs in disease development. Finally, we discuss the therapeutic potential of ALDHs in diseases, especially in tumor therapy with an emphasis on their clinical implications.
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Affiliation(s)
- Jie Xia
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Siqin Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjingChina
| | - Lixing Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co‐laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical CollegeFudan UniversityShanghaiChina
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14
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Kanai M, Elzur R, Zhou W, Daly MJ, Finucane HK. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution. CELL GENOMICS 2022; 2:100210. [PMID: 36643910 PMCID: PMC9839193 DOI: 10.1016/j.xgen.2022.100210] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/19/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022]
Abstract
Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10-4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.
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Affiliation(s)
- Masahiro Kanai
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02142, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Roy Elzur
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02142, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Wei Zhou
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02142, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Mark J. Daly
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02142, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Hilary K. Finucane
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02142, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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15
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Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248773. [PMID: 36557906 PMCID: PMC9781114 DOI: 10.3390/molecules27248773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening of FDA-approved drugs, hitting potent inhibitors against ALDH2. Using MD-derived conformations as receptors, butenafine (net charge q = +1 e) and olaparib (q = 0) were selected as promising compounds with a low toxicity and a binding strength equal to or stronger than previously reported potent inhibitors of daidzin and CVT-10216. A few negatively charged compounds were also hit from the docking with the Autodock Vina software, while the MM-PBSA analysis yielded positive binding energies (unfavorable binding) for these compounds, mainly owing to electrostatic repulsion in association with a negatively charged receptor (q = -6 e for ALDH2 plus the cofactor NAD+). This revealed a deficiency of the Vina scoring in dealing with strong charge-charge interactions between binding partners, due to its built-in protocol of not using atomic charges for electrostatic interactions. These observations indicated a requirement of further verification using MD and/or MM-PBSA after docking prediction. The identification of key residues for the binding implied that the receptor residues at the bottom and entrance of the substrate-binding hydrophobic tunnel were able to offer additional interactions with different inhibitors such as π-π, π-alkyl, van der Waals contacts, and polar interactions, and that the rational use of these interactions is beneficial to the design of potent inhibitors against ALDH2.
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16
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Nieto SJ, Harding MJ, Nielsen DA, Kosten TA. Paternal alcohol exposure has task- and sex-dependent behavioral effect in offspring. Alcohol Clin Exp Res 2022; 46:2191-2202. [PMID: 36281832 DOI: 10.1111/acer.14964] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Endophenotypes for alcohol use disorder are well known and may reflect paternal exposure effects passed down to offspring via epigenetic mechanisms. Previously, we showed that paternal alcohol exposure prior to conception attenuates the acquisition of operant alcohol self-administration. We now test whether paternal alcohol exposure alters their offsprings' behavioral responses to alcohol (endophenotypes) and global DNA methylation levels in reward-related brain regions. METHODS Adult male rats were exposed to alcohol vapors or air for 6 weeks and mated with alcohol-naïve females 8 weeks later. Adult male and female offspring of the alcohol- and control-sired litters were tested on three behaviors 30 m after gavage with water or alcohol (1.5 g/kg): open field, elevated plus maze, and accelerating rotarod. Global DNA methylation levels in sperm, nucleus accumbens, and prefrontal cortex were examined in male sires and in another group of offspring. RESULTS Alcohol-sired males showed less anxiety-like behavior in the elevated plus maze that was not affected by alcohol administration. By contrast, alcohol had anxiolytic effects in the open field in male offspring only with no paternal alcohol effect. Neither paternal alcohol exposure nor alcohol administration altered locomotor activity in either sex. Sex-specific effects of paternal alcohol exposure were seen in the rotarod test. Alcohol-sired male offspring showed blunted sensitivity to the alcohol's motor-impairing effects, whereas alcohol-sired female offspring showed enhanced sensitivity. Global DNA methylation was altered in the sperm of alcohol-exposed males, but no changes were seen in their offspring. CONCLUSIONS Paternal alcohol exposure prior to conception has sex- and task-dependent effects on unconditioned behaviors in their offspring.
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Affiliation(s)
- Steven J Nieto
- Department of Psychology, University of Houston, Houston, Texas, USA
| | | | | | - Therese A Kosten
- Department of Psychology, University of Houston, Houston, Texas, USA
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17
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He Z, Guo Q, Ling Y, Hong C, Liu Y, Jin X, Thanaporn P, Zhao D, Wang L, Liu L, Yan LL. Aldehyde dehydrogenase 2 rs671 polymorphism and multiple diseases: protocol for a quantitative umbrella review of meta-analyses. Syst Rev 2022; 11:185. [PMID: 36050775 PMCID: PMC9438126 DOI: 10.1186/s13643-022-02050-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/08/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The mutant allele (*2) of aldehyde dehydrogenase type 2 (ALDH2) caused by a single nucleotide variant (rs671) inhibits enzymatic activity and is associated with multiple diseases. In recent years, an explosive number of original studies and meta-analyses have been conducted to examine the associations of ALDH2 rs671 polymorphism with diseases. Due to conflicting results, the overall associations of ALDH2 rs671 polymorphism and multiple diseases remain unclear. METHODS A quantitative umbrella review will be conducted on meta-analyses of genetic association studies to examine the pleiotropic effects of ALDH2 rs671, mainly including cardio-cerebral vascular disease, diabetes mellitus, cancer, neurodegenerative disease, and alcohol-induced medical disease. A search of relevant literature according to comprehensive search strategies will be performed on studies published before July 1st, 2022 in PubMed, MEDLINE Ovid, Embase, Cochrane Database of Systematic Reviews, and Web of Science. Study selection, data extraction, methodology quality assessment, and strength of evidence assessment will be conducted by two reviewers independently and in duplicate. Included meta-analyses will be grouped by outcomes. Data conflicts and overlap between meta-analyses will be managed through updated standardized and customized methods including the calculation of CCA for study selection reference, application of Doi plots to assess small-study effects and others. Evidence from included meta-analyses will be quantitatively synthesized by overlap-corrected analyses and meta-analysis using primary studies. DISCUSSION This umbrella review is expected to generate systematic evidence on the association between ALDH2 rs671 and diseases. Specific approaches were developed to address key challenges in conducting an umbrella review, including assessment tools of methodology and evidence quality of meta-analyses, methods to manage overlap between meta-analyses, a "stop-light" plot to summarize key findings. These approaches provide applicable methods for future umbrella reviews of meta-analyses on genetic association studies. TRIAL REGISTRATION CRD42021223812.
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Affiliation(s)
- Zhengting He
- Global Health Research Center, Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China.,Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD, 21205, USA
| | - Qi Guo
- Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China
| | - Yikai Ling
- Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China
| | - Chuan Hong
- Department of Biostatistics & Bioinformatics, Duke University, 2424 Erwin Road, Durham, NC, 27705, USA
| | - Yuqing Liu
- Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China
| | - Xurui Jin
- MindRank AI Ltd., Hangzhou, Zhejiang, 310000, China
| | - Porama Thanaporn
- Department of Internal Medicine, University of Michigan Medical School, 1301 Catherine St, Ann Arbor, MI, 48109, USA
| | - Duan Zhao
- Global Health Research Center, Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China.,School of Public Health, Hong Kong University, 7 Sassoon Road, Pokfulam, Hong Kong
| | - Leiting Wang
- Global Health Research Center, Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China
| | - Liang Liu
- Global Health Research Center, Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China
| | - Lijing L Yan
- Global Health Research Center, Duke Kunshan University, No. 8 Duke Avenue, Kunshan, Jiangsu, 215316, China. .,Duke Global Health Institute, Duke University, 310 Trent Drive, Durham, NC, 27710, USA. .,School of Public Health, Wuhan University, No. 115 Donghu Road, Wuhan, Hubei, 430071, China. .,Institute for Global Health and Development, Peking University, No. 5 Yiheyuan Road, Beijing, 100871, China.
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18
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Zhou H, Kalayasiri R, Sun Y, Nuñez YZ, Deng HW, Chen XD, Justice AC, Kranzler HR, Chang S, Lu L, Shi J, Sanichwankul K, Mutirangura A, Malison RT, Gelernter J. Genome-wide meta-analysis of alcohol use disorder in East Asians. Neuropsychopharmacology 2022; 47:1791-1797. [PMID: 35094024 PMCID: PMC9372033 DOI: 10.1038/s41386-022-01265-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/22/2021] [Accepted: 12/29/2021] [Indexed: 12/14/2022]
Abstract
Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ~30 AUD risk genes in European populations, but many fewer in East Asians. We conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from five cohorts: (1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP) sample; (2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort; (3) AD in a Han Chinese-Cyto (array) cohort; and (4) two AD Thai cohorts. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4464 East Asians (Genetic Epidemiology Research in Adult Health and Aging (GERA)). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS. Two risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, SE = 0.067, p = 2.47 × 10-10) and nominally associated with pack years of smoking (beta = 0.09, SE = 0.05, p = 4.52 × 10-2) and ever vs. never smoking (beta = 0.06, SE = 0.02, p = 1.14 × 10-2). This is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.
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Affiliation(s)
- Hang Zhou
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Rasmon Kalayasiri
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Psychiatry, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yan Sun
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Yaira Z Nuñez
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Hong-Wen Deng
- Center for Biomedical Informatics and Genomics, School of Medicine, Tulane University, New Orleans, LA, USA
| | - Xiang-Ding Chen
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Amy C Justice
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, USA
| | - Henry R Kranzler
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
| | - Suhua Chang
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Lin Lu
- National Institute on Drug Dependence, Peking University, Beijing, China
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Jie Shi
- National Institute on Drug Dependence, Peking University, Beijing, China
| | | | - Apiwat Mutirangura
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Robert T Malison
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
| | - Joel Gelernter
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
- Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
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de Marco A, Scozia G, Manfredi L, Conversi D. A Systematic Review of Genetic Polymorphisms Associated with Bipolar Disorder Comorbid to Substance Abuse. Genes (Basel) 2022; 13:genes13081303. [PMID: 35893041 PMCID: PMC9330731 DOI: 10.3390/genes13081303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/09/2023] Open
Abstract
It is currently unknown which genetic polymorphisms are involved in substance use disorder (SUD) comorbid with bipolar disorder (BD). The research on polymorphisms in BD comorbid with SUD (BD + SUD) is summarized in this systematic review. We looked for case-control studies that genetically compared adults and adolescents with BD and SUD, healthy controls, and BD without SUD. PRISMA was used to create our protocol, which is PROSPERO-registered (identification: CRD4221270818). The following bibliographic databases were searched indefinitely until December 2021 to identify potentially relevant articles: PubMed, PsycINFO, Scopus, and Web of Science. This systematic review, after the qualitative analysis of the study selection, included 17 eligible articles. In the selected studies, 66 polymorphisms in 29 genes were investigated. The present work delivers a group of potentially valuable genetic polymorphisms associated with BD + SUD: rs11600996 (ARNTL), rs228642/rs228682/rs2640909 (PER3), PONQ192R (PON1), rs945032 (BDKRB2), rs1131339 (NR4A3), and rs6971 (TSPO). It is important to note that none of those findings have been confirmed by two or more studies; thus, we believe that all the polymorphisms identified in this review require additional evidence to be confirmed.
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Affiliation(s)
- Adriano de Marco
- Department of Psychology, Università degli Studi di Roma ‘La Sapienza’, 00185 Rome, Italy; (A.d.M.); (G.S.); (L.M.)
| | - Gabriele Scozia
- Department of Psychology, Università degli Studi di Roma ‘La Sapienza’, 00185 Rome, Italy; (A.d.M.); (G.S.); (L.M.)
- PhD Program in Behavioral Neuroscience, Università degli Studi di Roma ‘La Sapienza’, 00185 Rome, Italy
| | - Lucia Manfredi
- Department of Psychology, Università degli Studi di Roma ‘La Sapienza’, 00185 Rome, Italy; (A.d.M.); (G.S.); (L.M.)
| | - David Conversi
- Department of Psychology, Università degli Studi di Roma ‘La Sapienza’, 00185 Rome, Italy; (A.d.M.); (G.S.); (L.M.)
- Correspondence:
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20
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Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review. Antioxidants (Basel) 2022; 11:antiox11071374. [PMID: 35883865 PMCID: PMC9311529 DOI: 10.3390/antiox11071374] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative stress is still not fully elucidated. However, ethanol metabolism has been associated with increased oxidative stress through alcohol dehydrogenase, the microsomal ethanol oxidation system, and catalase metabolic pathways. We searched the PubMed and genome-wide association studies (GWAS) catalog databases to review the literature systematically and summarized the findings focusing on AUD and alcohol abstinence in relation to oxidative stress. In addition, we reviewed the ClinicalTrials.gov resource of the US National Library of Medicine to identify all ongoing and completed clinical trials that include therapeutic interventions based on antioxidants. The retrieved clinical and preclinical studies show that oxidative stress impacts AUD through genetics, alcohol metabolism, inflammation, and neurodegeneration.
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21
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Chen Y, Liu H, Yu Z, Yang Y, Huang Q, Deng C, Rao H, Wu H. ALDH2 Polymorphism rs671 *1/*2 Genotype is a Risk Factor for the Development of Alcoholic Liver Cirrhosis in Hakka Alcoholics. Int J Gen Med 2022; 15:4067-4077. [PMID: 35450031 PMCID: PMC9017692 DOI: 10.2147/ijgm.s356761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 04/05/2022] [Indexed: 01/19/2023] Open
Abstract
Background Alcoholics are prone to alcoholic cirrhosis (ALC). Aldehyde dehydrogenase 2 (ALDH2) is involved in alcohol metabolism. Herein, the relationship between ALDH2 genotypes and ALC was analyzed among Hakka alcoholics in southern China. Methods A total of 213 alcoholics and 214 non-alcoholics were included in the study. The ALDH2 gene rs671 polymorphism was analyzed, life history, disease history, and auxiliary examination results of these participants were collected. Results The alcoholics had higher level of total serum protein, and serum globulin, lower level of serum albumin, serum albumin/globulin ratio, serum prealbumin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) than non-alcoholics. In the 213 alcoholics, 180 developed ALC. There were 206 non-ALC persons in the 214 non-alcoholics. The proportion of the ALDH2 rs671 G/G homozygous (*1/*1) was significantly lower in ALC patients (83.3%) than that of other groups (100.0% in non-ALC in alcoholics, 95.6% in non-ALC in non-alcoholics), while the proportion of the G/A heterozygous (*1/*2) was significantly higher in ALC patients (16.7%) than that of other groups (0% in non-ALC in alcoholics, 4.4% in non-ALC in non-alcoholics). Logistic regression analysis indicated that participants with low level of NLR (adjusted OR 5.543, 95% CI 2.964–10.368, P<0.001), LMR (adjusted OR 9.256, 95% CI 4.740–18.076, P<0.001), and PLR (adjusted OR 6.047, 95% CI 3.372–10.845, P<0.001), and ALDH2 G/A genotype (adjusted OR 6.323, 95% CI 2.477–16.140, P<0.001) had a significantly higher risk of ALC. Conclusion ALDH2 polymorphism rs671 *1/*2 genotype is a potential risk factor for the development of ALC among Hakka alcoholics.
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Affiliation(s)
- Yijin Chen
- Department of Gastroenterology, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Hongtao Liu
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Department of Gastrointestinal Surgery, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Zhikang Yu
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Yang Yang
- Department of Gastroenterology, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Qingyan Huang
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Changqing Deng
- Department of Gastroenterology, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Hui Rao
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
| | - Heming Wu
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People's Republic of China
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22
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Shang D, Wang P, Tang W, Mo R, Lai R, Lu J, Li Z, Wang X, Cai W, Wang H, Zhao G, Xie Q, Xiang X. Genetic Variations of ALDH (rs671) Are Associated With the Persistence of HBV Infection Among the Chinese Han Population. Front Med (Lausanne) 2022; 9:811639. [PMID: 35237626 PMCID: PMC8882735 DOI: 10.3389/fmed.2022.811639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
Alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), members of the alcohol dehydrogenase family, have important roles in liver diseases. The roles of the polymorphisms of ADH1B rs1229984 and ALDH2 rs671 in hepatitis B virus (HBV) susceptibility and persistent infection were investigated in the present study. Total 1,034 patients with hepatitis B [99 acute hepatitis B (AHB), 521 chronic hepatitis B (CHB), 158 acute-on-chronic liver failure (ACLF), 159 liver cirrhosis (LC), and 97 hepatocellular carcinoma (HCC)] and 1,262 healthy controls (HCs) of the Chinese Han population were recruited, and single nucleotide polymorphisms (SNPs) of rs671 and rs1229984 were genotyped. Independent and joint roles of rs671 and rs1229984 in HBV infection were analyzed. The results showed that rs671 genotypes had a significantly different distribution among different subgroups. Compared with HCs, the frequency of rs671-AA genotype was higher in hepatitis B individuals, especially in the CHB group [adjusted OR (95%CI) = 1.899 (1.232–2.928), p = 0.003, in the co-dominant model], which showed a significant positive association. It was further confirmed that CHB individuals who carried ALDH2 rs671-AA genotype had a higher risk of persistent HBV infection and higher HBV-DNA quantitation compared with those with GG/GA genotype. In addition, the rs671-AA genotype might predict HCC incidence in patients with CHB. There were no different distributions of alleles or genotypes in rs671 mutant among AHB, ACLF, LC, or HCC groups compared with HCs. These data suggested the possible hazardous role of rs671-AA variant in HBV infection and persistence.
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Affiliation(s)
- Dabao Shang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Peng Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Weiliang Tang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ruidong Mo
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rongtao Lai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jie Lu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ziqiang Li
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Cai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hui Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Gangde Zhao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- *Correspondence: Gangde Zhao
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Qing Xie
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Translational Laboratory of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Xiaogang Xiang
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Balakrishnan R, Mohammed V, Veerabathiran R. The role of genetic mutation in alcoholic liver disease. EGYPTIAN LIVER JOURNAL 2022; 12:14. [DOI: 10.1186/s43066-022-00175-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 01/26/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Alcoholic liver disease (ALD) is the world’s most common type of liver disease caused due to overconsumption of alcohol. The liver supports the best level of tissue damage by hefty drinking since it is the binding site of ethanol digestion. This disease can progress to alcoholic steatohepatitis from alcoholic fatty liver, which implies steatosis has become the most punctual reaction to hefty drinking and is portrayed by the deposition of fat hepatocytes. In addition, steatosis can advance to steatohepatitis, a more extreme, provocative sort of liver damage described by hepatic inflammation. Constant and unnecessary liquor utilization delivers a wide range of hepatic sores, fibrosis and cirrhosis, and sometimes hepatocellular carcinoma. Most people consuming > 40 g of liquor each day create alcoholic fatty liver (AFL); notwithstanding, just a subset of people will grow further developed infection. Hereditary, epigenetic, and non-hereditary components may clarify the impressive interindividual variety in the ALD phenotype.
Main body
This systematic review is to classify new candidate genes associated with alcoholic liver disorders, such as RASGRF2, ALDH2, NFE2L2, ADH1B, PNPLA3, DRD2, MTHFR, TM6SF2, IL1B, and CYP2E1, MBOAT7 as well as to revise the functions of each gene in its polymorphic sequence. The information obtained from the previously published articles revealed the crucial relationship between the genes and ALD and discussed each selected gene’s mechanism.
Conclusion
The aim of this review is to highlight the candidate genes associated with the ALD, and the evidence of this study is to deliberate the part of genetic alterations and modifications that can serve as an excellent biological maker, risk predictors, and therapeutic targets for this disease.
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Veerappa A, Pendyala G, Guda C. A systems omics-based approach to decode substance use disorders and neuroadaptations. Neurosci Biobehav Rev 2021; 130:61-80. [PMID: 34411560 PMCID: PMC8511293 DOI: 10.1016/j.neubiorev.2021.08.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/23/2021] [Accepted: 08/14/2021] [Indexed: 11/15/2022]
Abstract
Substance use disorders (SUDs) are a group of neuropsychiatric conditions manifesting due to excessive dependence on potential drugs of abuse such as psychostimulants, opioids including prescription opioids, alcohol, inhalants, etc. Experimental studies have generated enormous data in the area of SUDs, but outcomes from such data have remained largely fragmented. In this review, we attempt to coalesce these data points providing an important first step towards our understanding of the etiology of SUDs. We propose and describe a 'core addictome' pathway that behaves central to all SUDs. Besides, we also have made some notable observations paving way for several hypotheses; MECP2 behaves as a master switch during substance use; five distinct gene clusters were identified based on respective substance addiction; a central cluster of genes serves as a hub of the addiction pathway connecting all other substance addiction clusters. In addition to describing these findings, we have emphasized the importance of some candidate genes that are of substantial interest for further investigation and serve as high-value targets for translational efforts.
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Affiliation(s)
- Avinash Veerappa
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Gurudutt Pendyala
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Center for Biomedical Informatics Research and Innovation, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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25
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Abstract
Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine.
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Affiliation(s)
- Joseph D. Deak
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA
| | - Emma C. Johnson
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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26
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Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption. Sci Rep 2021; 11:13690. [PMID: 34211048 PMCID: PMC8249592 DOI: 10.1038/s41598-021-93086-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/18/2021] [Indexed: 12/19/2022] Open
Abstract
Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.
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Zhang H, Xia Y, Wang F, Luo M, Yang K, Liang S, An S, Wu S, Yang C, Chen D, Xu M, Cai M, To KKW, Fu L. Aldehyde Dehydrogenase 2 Mediates Alcohol-Induced Colorectal Cancer Immune Escape through Stabilizing PD-L1 Expression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003404. [PMID: 34026438 PMCID: PMC8132160 DOI: 10.1002/advs.202003404] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 02/21/2021] [Indexed: 05/06/2023]
Abstract
Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD-1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD-L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD-L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD-L1 protein expression by physically interacting with the intracellular segment of PD-L1 and inhibiting its proteasome-dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD-L1 protein in CRC cells and promotes tumor-infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti-PD-1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol-mediated tumor escape from immunity surveillance and promote tumor progression.
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Affiliation(s)
- Hong Zhang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Yuhui Xia
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Fang Wang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Min Luo
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Ke Yang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Shaobo Liang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Sainan An
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Shaocong Wu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Chuan Yang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Da Chen
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Meng Xu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Muyan Cai
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
| | - Kenneth K. W. To
- School of PharmacyFaculty of MedicineThe Chinese University of Hong KongHong KongChina
| | - Liwu Fu
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangzhou510060China
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de Melo-Martin I, Crystal RG. Primum Non Nocere: Should Gene Therapy Be Used to Prevent Potentially Fatal Disease but Enable Potentially Destructive Behavior? Hum Gene Ther 2021; 32:529-534. [PMID: 33752441 DOI: 10.1089/hum.2021.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Aldehyde dehydrogenase 2 (ALDH2) deficiency constitutes one of the most common hereditary enzyme deficiencies, affecting 35% to 40% of East Asians and 8% of the world population. It causes the well-known Asian Alcohol Flush Syndrome, characterized by facial flushing, palpitation, tachycardia, nausea, and other unpleasant feelings when alcohol is consumed. It is also associated with a marked increase in the risk of a variety of serious disorders, including esophageal cancer and osteoporosis. Our recent studies with murine models have demonstrated that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) will correct the deficiency state and prevent alcohol-induced abnormalities of the esophagus and bone. If successful in humans, such strategy would reduce the increased risk-associated disorders such as esophageal cancer and osteoporosis, but also prevent the Asian Alcohol Flush Syndrome. This treatment thus raises ethical concerns: although it would potentially prevent fatal disease, it could also allow affected individuals to drink alcohol without suffering the Asian Alcohol Flush Syndrome and, hence, potentially enable personal destructive behavior. Here we explore the ethical arguments against the development of a gene therapy for ALDH2 deficiency and we find them wanting. We contend that development of such treatments is ethically appropriate and should be part and parcel of the solutions offered against the condition.
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Affiliation(s)
| | - Ronald G Crystal
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA
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Wang Q, Chang B, Li X, Zou Z. Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis. J Clin Transl Hepatol 2021; 9:90-98. [PMID: 33604259 PMCID: PMC7868706 DOI: 10.14218/jcth.2020.00104] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease. ALDH2 gene mutations exist in about 8% of the world's population, with the incidence reaching 45% in East Asia. The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde, facilitating the progression of other liver diseases, including non-alcoholic fatty liver diseases, viral hepatitis and hepatocellular carcinoma, through adduct formation and inflammatory responses. In this review, we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases, with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.
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Affiliation(s)
- Qiaoling Wang
- Peking University, 302 Clinical Medical School, Beijing, China
- Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Binxia Chang
- Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiaoyan Li
- Anhui Medical University, Hefei, Anhui, China
| | - Zhengsheng Zou
- Peking University, 302 Clinical Medical School, Beijing, China
- Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Correspondence to: Zhengsheng Zou, The Center for Diagnosis and Treatment of Non-Infectious Liver Disease, The General Hospital of Chinese People’s Liberation Army No. 5 Medical Science Center, No. 100 Xisihuan Middle Road, Beijing 100039, China. E-mail:
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Mathkar PP, Chen X, Sulovari A, Li D. Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes. Viruses 2021; 13:v13020245. [PMID: 33557409 PMCID: PMC7915589 DOI: 10.3390/v13020245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions.
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Affiliation(s)
- Pranav P. Mathkar
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA; (P.P.M.); (A.S.)
| | - Xun Chen
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA; (P.P.M.); (A.S.)
- Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto 606-8501, Japan
- Correspondence: (X.C.); (D.L.)
| | - Arvis Sulovari
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA; (P.P.M.); (A.S.)
- Cajal Neuroscience Inc., Seattle, WA 98102, USA
| | - Dawei Li
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA; (P.P.M.); (A.S.)
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Correspondence: (X.C.); (D.L.)
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Li W, Thygesen JH, O'Brien NL, Heydtmann M, Smith I, Degenhardt F, Nöthen MM, Morgan MY, Bass NJ, McQuillin A. The influence of regression models on genome-wide association studies of alcohol dependence: a comparison of binary and quantitative analyses. Psychiatr Genet 2021; 31:13-20. [PMID: 33290381 DOI: 10.1097/ypg.0000000000000268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Genome-wide association studies (GWAS) of alcohol dependence syndrome (ADS) offer a platform to detect genetic risk loci. However, the majority of the ADS GWAS undertaken, to date, have utilized a case-control design and have failed to identify consistently replicable loci with the exception of protective variants within the alcohol metabolizing genes, notably ADH1B. The ADS phenotype shows considerable variability which means that the use of quantitative variables as a proxy for the severity of ADS has the potential to facilitate identification of risk loci by increasing statistical power. The current study aims to examine the influences of using binary and adjusted quantitative measures of ADS on GWAS outcomes and on calculated polygenic risk scores (PRS). METHODS A GWAS was performed in 1251 healthy controls with no history of excess alcohol use and 739 patients with ADS classified using binary DMS-IV criteria. Two additional GWAS were undertaken using a quantitative score based on DSM-IV criteria, which were applied assuming both normal and non-normal distributions of the phenotypic variables. PRS analyses were performed utilizing the data from the binary and the quantitative trait analyses. RESULTS No associations were identified at genome-wide significance in any of the individual GWAS; results were comparable in all three. The top associated single nucleotide polymorphism was located on the alcohol dehydrogenase gene cluster on chromosome 4, consistent with previous ADS GWAS. The quantitative trait analysis adjusted for the distribution of the criterion score and the associated PRS had the smallest standard errors and thus the greatest precision. CONCLUSION Further exploitation of the use of qualitative trait analysis in GWAS in ADS is warranted.
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Affiliation(s)
- Wenqianglong Li
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London
| | - Johan Hilge Thygesen
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London
| | - Niamh Louise O'Brien
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London
| | - Mathis Heydtmann
- Royal Alexandria Hospital, NHS Greater Glasgow and Clyde, Paisley
| | - Iain Smith
- Glasgow Addiction Services, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Franziska Degenhardt
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn
- Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany
| | - Markus Maria Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn
| | - Marsha Yvonne Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Nicholas James Bass
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London
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Blázovics A. Alcoholic liver disease. INFLUENCE OF NUTRIENTS, BIOACTIVE COMPOUNDS, AND PLANT EXTRACTS IN LIVER DISEASES 2021:57-82. [DOI: 10.1016/b978-0-12-816488-4.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ikeda K, Ide S, Takahashi-Omoe H, Minami M, Miyata H, Kawato M, Okamoto H, Kikuchi T, Saito Y, Shirao T, Sekino Y, Murai T, Matsumoto T, Iseki M, Nishitani Y, Sumitani M, Takahashi H, Yamawaki S, Isa T, Kamio Y. Required research activities to overcome addiction problems in Japan. TAIWANESE JOURNAL OF PSYCHIATRY 2021. [DOI: 10.4103/tpsy.tpsy_3_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Ceci FM, Ferraguti G, Petrella C, Greco A, Ralli M, Iannitelli A, Carito V, Tirassa P, Chaldakov GN, Messina MP, Ceccanti M, Fiore M. Nerve Growth Factor in Alcohol Use Disorders. Curr Neuropharmacol 2020; 19:45-60. [PMID: 32348226 PMCID: PMC7903493 DOI: 10.2174/1570159x18666200429003239] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/19/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022] Open
Abstract
The nerve growth factor (NGF) belongs to the family of neurotrophic factors. Initially discovered as a signaling molecule involved in the survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons, it also participates in the regulation of the immune system and endocrine system. NGF biological activity is due to the binding of two classes of receptors: the tropomyosin-related kinase A (TrkA) and the low-affinity NGF pan-neurotrophin receptor p75. Alcohol Use Disorders (AUD) are one of the most frequent mental disorders in developed countries, characterized by heavy drinking, despite the negative effects of alcohol on brain development and cognitive functions that cause individual’s work, medical, legal, educational, and social life problems. In addition, alcohol consumption during pregnancy disrupts the development of the fetal brain causing a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). The rationale of this review is to describe crucial findings on the role of NGF in humans and animals, when exposed to prenatal, chronic alcohol consumption, and on binge drinking.
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Affiliation(s)
- Flavio Maria Ceci
- Department of Experimental Medicine, Sapienza University Hospital of Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University Hospital of Rome, Italy
| | - Carla Petrella
- Institute of Biochemistry and Cell Biology, Section of Neurobiology, National Research Council (IBBC-CNR), Rome, Italy
| | - Antonio Greco
- Department of Sense Organs, Sapienza University Hospital of Rome, Italy
| | - Massimo Ralli
- Department of Sense Organs, Sapienza University Hospital of Rome, Italy
| | - Angela Iannitelli
- Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, Italy
| | - Valentina Carito
- Institute of Biochemistry and Cell Biology, Section of Neurobiology, National Research Council (IBBC-CNR), Rome, Italy
| | - Paola Tirassa
- Institute of Biochemistry and Cell Biology, Section of Neurobiology, National Research Council (IBBC-CNR), Rome, Italy
| | - George N Chaldakov
- Department of Anatomy and Cell Biology, Medical University, Varna, Bulgaria
| | | | - Mauro Ceccanti
- Centro Riferimento Alcologico Regione Lazio, Sapienza University of Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, Section of Neurobiology, National Research Council (IBBC-CNR), Rome, Italy
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A critical assessment of the potential of pharmacological modulation of aldehyde dehydrogenases to treat the diseases of bone loss. Eur J Pharmacol 2020; 886:173541. [PMID: 32896553 DOI: 10.1016/j.ejphar.2020.173541] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 12/19/2022]
Abstract
Chronic alcoholism (CA) decreases bone mass and increases the risk of hip fracture. Alcohol and its main metabolite, acetaldehyde impairs osteoblastogenesis by increasing oxidative stress. Aldehyde dehydrogenase (ALDH) is the rate-limiting enzyme in clearing acetaldehyde from the body. The clinical relevance of ALDH in skeletal function has been established by the discovery of single nucleotide polymorphism, SNP (rs671) in the ALDH2 gene giving rise to an inactive form of the enzyme (ALDH2*2) that causes increased serum acetaldehyde and osteoporosis in the affected individuals. Subsequent mouse genetics studies have replicated human phenotype in mice and confirmed the non-redundant role of ALDH2 in bone homeostasis. The activity of ALDH2 is amenable to pharmacological modulation. ALDH2 inhibition by disulfiram (DSF) and activation by alda-1 cause reduction and induction of bone formation, respectively. DSF also inhibits peak bone mass accrual in growing rats. On the other hand, DSF showed an anti-osteoclastogenic effect and protected mice from alcohol-induced osteopenia by inhibiting ALDH1a1 in bone marrow monocytes. Besides DSF, there are several classes of ALDH inhibitors with disparate skeletal effects. Alda-1, the ALDH2 activator induced osteoblast differentiation by increasing bone morphogenic protein 2 (BMP2) expression via ALDH2 activation. Alda-1 also restored ovariectomy-induced bone loss. The scope of structure-activity based studies with ALDH2 and the alda-1-like molecule could lead to the discovery of novel osteoanabolic molecules. This review will critically discuss the molecular mechanism of the ethanol and its principal metabolite, acetaldehyde in the context of ALDH2 in bone cells, and skeletal homeostasis.
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Sutoh Y, Hachiya T, Suzuki Y, Komaki S, Ohmomo H, Kakisaka K, Wang T, Takikawa Y, Shimizu A. ALDH2 genotype modulates the association between alcohol consumption and AST/ALT ratio among middle-aged Japanese men: a genome-wide G × E interaction analysis. Sci Rep 2020; 10:16227. [PMID: 33004991 PMCID: PMC7530747 DOI: 10.1038/s41598-020-73263-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 09/11/2020] [Indexed: 12/19/2022] Open
Abstract
Liver tests (LT), especially to measure AST, ALT and GGT levels, are widely used to evaluate the risk of alcohol-related liver disease (ALD). In this study, we investigated the potential genetic factors that modulate the association between LTs and alcohol consumption. We conducted a genome-wide interaction meta-analysis in 7856 Japanese subjects from Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) study recruited in 2013, and identified 2 loci (12q24 and 2p16) with genome-wide significance (P > 5 × 10-8). The significant variants in the 12q24 included rs671, a variant associated with alcohol intolerance and located at a coding exon of ALDH2. We found that the amount of alcohol consumption was associated with increased level AST/ALT ratio among the subjects with the rs671 GA genotype. The elevated AST/ALT ratio among subjects with moderate-to-high levels of drinking behavior and the rs671 GA genotype was due to decreased levels of ALT, which was not accompanied with significant differences in AST levels. Although the interaction effect was significant in both men and women, the effect was much larger in men. Our results suggest that the impact of alcohol consumption on LT varies according to the ALDH2 genotype, providing an insight for the accurate screening of ALD in drinkers with the rs671 GA genotype.
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Affiliation(s)
- Yoichi Sutoh
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Tsuyoshi Hachiya
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
| | - Shohei Komaki
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Hideki Ohmomo
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
| | - Ting Wang
- Division of Biomedical Research and Development, Institute of Biomedical Sciences, Iwate Medical University, Morioka, Iwate, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
| | - Atsushi Shimizu
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan.
- Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan.
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Abstract
BACKGROUND Alcohol is consumed by over 2 billion people worldwide. It is a common substance of abuse and its use can lead to more than 200 disorders including hypertension. Alcohol has both acute and chronic effects on blood pressure. This review aimed to quantify the acute effects of different doses of alcohol over time on blood pressure and heart rate in an adult population. OBJECTIVES Primary objective To determine short-term dose-related effects of alcohol versus placebo on systolic blood pressure and diastolic blood pressure in healthy and hypertensive adults over 18 years of age. Secondary objective To determine short-term dose-related effects of alcohol versus placebo on heart rate in healthy and hypertensive adults over 18 years of age. SEARCH METHODS The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2019: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 2), in the Cochrane Library; MEDLINE (from 1946); Embase (from 1974); the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant articles regarding further published and unpublished work. These searches had no language restrictions. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing effects of a single dose of alcohol versus placebo on blood pressure (BP) or heart rate (HR) in adults (≥ 18 years of age). DATA COLLECTION AND ANALYSIS Two review authors (ST and CT) independently extracted data and assessed the quality of included studies. We also contacted trial authors for missing or unclear information. Mean difference (MD) from placebo with 95% confidence interval (CI) was the outcome measure, and a fixed-effect model was used to combine effect sizes across studies. MAIN RESULTS: We included 32 RCTs involving 767 participants. Most of the study participants were male (N = 642) and were healthy. The mean age of participants was 33 years, and mean body weight was 78 kilograms. Low-dose alcohol (< 14 g) within six hours (2 RCTs, N = 28) did not affect BP but did increase HR by 5.1 bpm (95% CI 1.9 to 8.2) (moderate-certainty evidence). Medium-dose alcohol (14 to 28 g) within six hours (10 RCTs, N = 149) decreased systolic blood pressure (SBP) by 5.6 mmHg (95% CI -8.3 to -3.0) and diastolic blood pressure (DBP) by 4.0 mmHg (95% CI -6.0 to -2.0) and increased HR by 4.6 bpm (95% CI 3.1 to 6.1) (moderate-certainty evidence for all). Medium-dose alcohol within 7 to 12 hours (4 RCTs, N = 54) did not affect BP or HR. Medium-dose alcohol > 13 hours after consumption (4 RCTs, N = 66) did not affect BP or HR. High-dose alcohol (> 30 g) within six hours (16 RCTs, N = 418) decreased SBP by 3.5 mmHg (95% CI -6.0 to -1.0), decreased DBP by 1.9 mmHg (95% CI-3.9 to 0.04), and increased HR by 5.8 bpm (95% CI 4.0 to 7.5). The certainty of evidence was moderate for SBP and HR, and was low for DBP. High-dose alcohol within 7 to 12 hours of consumption (3 RCTs, N = 54) decreased SBP by 3.7 mmHg (95% CI -7.0 to -0.5) and DBP by 1.7 mmHg (95% CI -4.6 to 1.8) and increased HR by 6.2 bpm (95% CI 3.0 to 9.3). The certainty of evidence was moderate for SBP and HR, and low for DBP. High-dose alcohol ≥ 13 hours after consumption (4 RCTs, N = 154) increased SBP by 3.7 mmHg (95% CI 2.3 to 5.1), DBP by 2.4 mmHg (95% CI 0.2 to 4.5), and HR by 2.7 bpm (95% CI 0.8 to 4.6) (moderate-certainty evidence for all). AUTHORS' CONCLUSIONS: High-dose alcohol has a biphasic effect on BP; it decreases BP up to 12 hours after consumption and increases BP > 13 hours after consumption. High-dose alcohol increases HR at all times up to 24 hours. Findings of this review are relevant mainly to healthy males, as only small numbers of women were included in the included trials.
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Affiliation(s)
- Sara Tasnim
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Chantel Tang
- Faculty of Health Sciences, McGill University, Montreal, Canada
| | - Vijaya M Musini
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - James M Wright
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
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Stickel F, Lutz P, Buch S, Nischalke HD, Silva I, Rausch V, Fischer J, Weiss KH, Gotthardt D, Rosendahl J, Marot A, Elamly M, Krawczyk M, Casper M, Lammert F, Buckley TWM, McQuillin A, Spengler U, Eyer F, Vogel A, Marhenke S, von Felden J, Wege H, Sharma R, Atkinson S, Franke A, Nehring S, Moser V, Schafmayer C, Spahr L, Lackner C, Stauber RE, Canbay A, Link A, Valenti L, Grove JI, Aithal GP, Marquardt JU, Fateen W, Zopf S, Dufour JF, Trebicka J, Datz C, Deltenre P, Mueller S, Berg T, Hampe J, Morgan MY. Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers. Hepatology 2020; 72:88-102. [PMID: 31630428 DOI: 10.1002/hep.30996] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 09/18/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). CONCLUSIONS Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.
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Affiliation(s)
- Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zürich, Switzerland
| | - Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Stephan Buch
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | | | - Ines Silva
- Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany
| | - Vanessa Rausch
- Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany
| | - Janett Fischer
- Division of Hepatology, Clinic and Polyclinic for Gastroenterology, Hepatology, Infectiology and Pneumology, University Clinic Leipzig, Leipzig, Germany
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Medical University of Heidelberg, Germany
| | - Daniel Gotthardt
- Department of Internal Medicine IV, Medical University of Heidelberg, Germany
| | - Jonas Rosendahl
- Department of Gastroenterology, University Hospital Halle/Saale, Germany
| | - Astrid Marot
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland
| | - Mona Elamly
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Markus Casper
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Thomas W M Buckley
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, UK
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, UK
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Florian Eyer
- Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Johann von Felden
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henning Wege
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rohini Sharma
- Department of Metabolism, Digestion & Reproduction, Division of Surgery and Cancer, Imperial College London, London, UK
| | - Stephen Atkinson
- Department of Metabolism, Digestion & Reproduction, Division of Surgery and Cancer, Imperial College London, London, UK
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Sophie Nehring
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | - Vincent Moser
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | - Clemens Schafmayer
- Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany
| | - Laurent Spahr
- Departments of Gastroenterology and Hepatology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
| | | | - Rudolf E Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Ali Canbay
- Ruhr-Universität Bochum, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany
| | - Alexander Link
- Ruhr-Universität Bochum, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Jane I Grove
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Jens U Marquardt
- Department of Medicine I, Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - Waleed Fateen
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Steffen Zopf
- Medical Department 1, University of Erlangen-Nuremberg, Germany
| | - Jean-Francois Dufour
- University Clinic for Visceral Surgery and Medicine, Inselspital, University of Berne, Berne, Switzerland
| | - Jonel Trebicka
- Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
| | - Christian Datz
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria
| | - Pierre Deltenre
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland
| | - Sebastian Mueller
- Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Berg
- Division of Hepatology, Clinic and Polyclinic for Gastroenterology, Hepatology, Infectiology and Pneumology, University Clinic Leipzig, Leipzig, Germany
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, UK
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Hibberd R, Golovina E, Farrow S, O'Sullivan JM. Genetic variants associated with alcohol dependence co-ordinate regulation of ADH genes in gastrointestinal and adipose tissues. Sci Rep 2020; 10:9897. [PMID: 32555468 PMCID: PMC7303195 DOI: 10.1038/s41598-020-66048-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 05/13/2020] [Indexed: 11/29/2022] Open
Abstract
GWAS studies have identified genetic variants associated with Alcohol Dependence (AD), but how they link to genes, their regulation and disease traits, remains largely unexplored. Here we integrated information on the 3D genome organization with expression quantitative loci (eQTLs) analysis, using CoDeS3D, to identify the functional impacts of single nucleotide polymorphisms associated with AD (p < 1 × 10-6). We report that 42% of the 285 significant tissue-specific regulatory interactions we identify were associated with four genes encoding Alcohol Dehydrogenase - ADH1A, ADH1B, ADH1C and ADH4. Identified eQTLs produced a co-ordinated regulatory action between ADH genes, especially between ADH1A and ADH1C within the subcutaneous adipose and gastrointestinal tissues. Five eQTLs were associated with regulatory motif alterations and tissue-specific histone marks consistent with these variants falling in enhancer and promoter regions. By contrast, few regulatory connections were identified in the stomach and liver. This suggests that changes in gene regulation associated with AD are linked to changes in tissues other than the primary sites of alcohol absorption and metabolism. Future work to functionally characterise the putative regulatory regions we have identified and their links to metabolic and regulatory changes in genes will improve our mechanistic understanding of AD disease development and progression.
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Affiliation(s)
- Rebecca Hibberd
- Liggins Institute, The University of Auckland, Auckland, New Zealand
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
- Natural Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Evgeniia Golovina
- Liggins Institute, The University of Auckland, Auckland, New Zealand
- A Better Start National Science Challenge, Auckland, New Zealand
| | - Sophie Farrow
- Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Justin M O'Sullivan
- Liggins Institute, The University of Auckland, Auckland, New Zealand.
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
- A Better Start National Science Challenge, Auckland, New Zealand.
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40
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Liu H, Ge W, Chen W, Kong X, Jian W, Wang A. Association between ALDH2 Gene Polymorphism and Late-onset Alzheimer Disease: An Up-to-date Meta-analysis. Curr Alzheimer Res 2020; 17:105-111. [PMID: 32183676 DOI: 10.2174/1567205017666200317102337] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 12/30/2019] [Accepted: 01/22/2020] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Previous case-control studies have focused on the relationship between ALDH2 gene polymorphism and late-onset Alzheimer's Disease (LOAD), but no definite unified conclusion has been reached. Therefore, the correlation between ALDH2 Glu504Lys polymorphism and LOAD remains controversial. To analyze the correlation between ALDH2 polymorphism and the risk of LOAD, we implemented this up-to-date meta-analysis to assess the probable association. METHODS Studies were searched through China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals, China Biology Medicine, PubMed, Cochrane Library, Clinical- Trials.gov, Embase, and MEDLINE from January 1, 1994 to December 31, 2018, without any restrictions on language and ethnicity. RESULTS Five studies of 1057 LOAD patients and 1136 healthy controls met our criteria for the analysis. Statistically, the ALDH2 GA/AA genotype was not linked with raising LOAD risk (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 0.96-2.28, p = 0.07). In subgroup analysis, the phenomenon that men with ALDH2*2 had higher risk for LOAD (OR = 1.72, 95%CI = 1.10-2.67, p = 0.02) was observed. CONCLUSION This study comprehends only five existing case-control studies and the result is negative. The positive trend might appear when the sample size is enlarged. In the future, more large-scale casecontrol or cohort studies should be done to enhance the association between ALDH2 polymorphism and AD or other neurodegenerative diseases.
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Affiliation(s)
- Haitao Liu
- Department of General Practice, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Wei Ge
- Department of General Practice, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Wei Chen
- Department of General Practice, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Xue Kong
- Department of General Practice, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Weiming Jian
- Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Anhui Wang
- Department of Epidemiology, School of Military Preventive Medicine, The Fourth Military Medical University, Xi'an 710032, China
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41
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Jiang Y, Zhang T, Kusumanchi P, Han S, Yang Z, Liangpunsakul S. Alcohol Metabolizing Enzymes, Microsomal Ethanol Oxidizing System, Cytochrome P450 2E1, Catalase, and Aldehyde Dehydrogenase in Alcohol-Associated Liver Disease. Biomedicines 2020; 8:50. [PMID: 32143280 PMCID: PMC7148483 DOI: 10.3390/biomedicines8030050] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/20/2020] [Accepted: 02/29/2020] [Indexed: 12/12/2022] Open
Abstract
Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system (cytochrome P450 2E1) and catalase. Acetaldehyde can form adducts which can interfere with cellular function, leading to alcohol-induced liver injury. The variants of alcohol metabolizing genes encode enzymes with varied kinetic properties and result in the different rate of alcohol elimination and acetaldehyde generation. Allelic variants of these genes with higher enzymatic activity are believed to be able to modify susceptibility to alcohol-induced liver injury; however, the human studies on the association of these variants and alcohol-associated liver disease are inconclusive. In addition to acetaldehyde, the shift in the redox state during alcohol elimination may also link to other pathways resulting in activation of downstream signaling leading to liver injury.
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Affiliation(s)
- Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA
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42
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Maruvada P, Lampe JW, Wishart DS, Barupal D, Chester DN, Dodd D, Djoumbou-Feunang Y, Dorrestein PC, Dragsted LO, Draper J, Duffy LC, Dwyer JT, Emenaker NJ, Fiehn O, Gerszten RE, B Hu F, Karp RW, Klurfeld DM, Laughlin MR, Little AR, Lynch CJ, Moore SC, Nicastro HL, O'Brien DM, Ordovás JM, Osganian SK, Playdon M, Prentice R, Raftery D, Reisdorph N, Roche HM, Ross SA, Sang S, Scalbert A, Srinivas PR, Zeisel SH. Perspective: Dietary Biomarkers of Intake and Exposure-Exploration with Omics Approaches. Adv Nutr 2020; 11:200-215. [PMID: 31386148 PMCID: PMC7442414 DOI: 10.1093/advances/nmz075] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.
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Affiliation(s)
- Padma Maruvada
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Johanna W Lampe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - David S Wishart
- Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, Alberta, Canada
| | - Dinesh Barupal
- West Coast Metabolomics Center, UC Davis Genome Center, University of California, Davis, Davis, CA, USA
| | - Deirdra N Chester
- Division of Nutrition, Institute of Food Safety and Nutrition at the National Institute of Food and Agriculture, USDA, Washington, DC, USA
| | - Dylan Dodd
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Yannick Djoumbou-Feunang
- Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, Alberta, Canada
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
| | - Lars O Dragsted
- Department of Nutrition, Exercise, and Sports, Section of Preventive and Clinical Nutrition, University of Copenhagen, Copenhagen, Denmark
| | - John Draper
- Institute of Biological Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, Ceredigion, United Kingdom
| | - Linda C Duffy
- National Institutes of Health, National Center for Complementary and Integrative Health, Bethesda, MD, USA
| | - Johanna T Dwyer
- National Institutes of Health, Office of Dietary Supplements, Bethesda, MD, USA
| | - Nancy J Emenaker
- National Institutes of Health, National Cancer Institute, Rockville, MD, USA
| | - Oliver Fiehn
- West Coast Metabolomics Center, UC Davis Genome Center, University of California, Davis, Davis, CA, USA
| | - Robert E Gerszten
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Frank B Hu
- Departments of Nutrition; Epidemiology and Statistics, Harvard TH Chan School of Public Health, Boston, MA, USA
- Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Robert W Karp
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - David M Klurfeld
- Department of Nutrition, Food Safety/Quality, USDA—Agricultural Research Service, Beltsville, MD, USA
| | - Maren R Laughlin
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - A Roger Little
- National Institutes of Health, National Institute on Drug Abuse, Bethesda, MD, USA
| | - Christopher J Lynch
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Steven C Moore
- National Institutes of Health, National Cancer Institute, Rockville, MD, USA
| | - Holly L Nicastro
- National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
| | - Diane M O'Brien
- Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA
| | - José M Ordovás
- Nutrition and Genomics Laboratory, Jean Mayer–USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Stavroula K Osganian
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Mary Playdon
- Department of Nutrition and Integrative Physiology, University of Utah and Division of Cancer Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Ross Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Daniel Raftery
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Helen M Roche
- Nutrigenomics Research Group, School of Public Health, Physiotherapy and Sports Science, UCD Institute of Food and Health, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland
| | - Sharon A Ross
- National Institutes of Health, National Cancer Institute, Rockville, MD, USA
| | - Shengmin Sang
- Laboratory for Functional Foods and Human Health, Center for Excellence in Post-Harvest Technologies, North Carolina A&T State University, North Carolina Research Campus, Nutrition Research Building, Kannapolis, NC, USA
| | - Augustin Scalbert
- International Agency for Research on Cancer, Nutrition and Metabolism Section, Biomarkers Group, Lyon, France
| | - Pothur R Srinivas
- National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
| | - Steven H Zeisel
- Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA
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Association Between the Polymorphism of Aldehyde Dehydrogenase 2 Gene and Cerebral Infarction in a Hakka Population in Southern China. Biochem Genet 2020; 58:322-334. [PMID: 32006143 DOI: 10.1007/s10528-020-09950-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 11/04/2019] [Indexed: 10/25/2022]
Abstract
Genetic factors play an important role in determining the susceptibility to ischemic stroke. Herein, we examined the association of an aldehyde dehydrogenase 2 (ALDH2) gene polymorphism with cerebral infarction. Patients with cerebral infarction (n = 963) and healthy controls (n = 921) were included. Genotyping was performed using gene chip platform analysis, and Sanger sequencing was used to confirm ALDH2 genotypes. The risk prediction of ALDH2 polymorphisms for cerebral infarction was examined under three genetic modes of inheritance. For males, ALDH2*2/*2 genotype was a significant risk factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 1.514, 95% CI 1.005-2.282, p = 0.047) and the recessive model (age-, smoking-, and drinking-adjusted OR 1.601, 95% CI 1.078-2.379, p = 0.020). However, for females, ALDH2*2/*2 genotype was a protective factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 0.450 95% CI 0.215-0.941, p = 0.034) and the recessive model (age-, smoking-, and drinking-adjusted OR 0.440, 95% CI 0.214-0.903, p = 0.025). Further, logistic regression analysis revealed that age, smoking, hypertension, hyperlipidemia, and hypercholesterolemia were significant risks for the presence of cerebral infarction. In conclusion, these findings support an association of ALDH2 gene polymorphisms with ischemic stroke in a Chinese Hakka population. In particular, homozygote ALDH2*2/*2 may be a risk factor for cerebral infarction in males, but contribute to reduced risk for cerebral infarction in females.
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van den Berg FF, Kempeneers MA, van Santvoort HC, Zwinderman AH, Issa Y, Boermeester MA. Meta-analysis and field synopsis of genetic variants associated with the risk and severity of acute pancreatitis. BJS Open 2019; 4:3-15. [PMID: 32011822 PMCID: PMC6996643 DOI: 10.1002/bjs5.50231] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 09/11/2019] [Indexed: 12/17/2022] Open
Abstract
Background Genetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP. Methods Online databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta‐analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false‐discovery probability were applied to assess credibility. Results Ninety‐six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta‐analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single‐nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility. Conclusion Genetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP.
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Affiliation(s)
- F F van den Berg
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - M A Kempeneers
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - H C van Santvoort
- Department of Surgery, St Antonius Hospital, Nieuwegein, the Netherlands.,Department of Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - A H Zwinderman
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Y Issa
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - M A Boermeester
- Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
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45
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Zaso MJ, Goodhines PA, Wall TL, Park A. Meta-Analysis on Associations of Alcohol Metabolism Genes With Alcohol Use Disorder in East Asians. Alcohol Alcohol 2019; 54:216-224. [PMID: 30834931 DOI: 10.1093/alcalc/agz011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/27/2019] [Accepted: 02/21/2019] [Indexed: 12/20/2022] Open
Abstract
AIMS The current meta-analysis tested independent and composite associations of three commonly studied alcohol metabolism alleles with alcohol use disorder (AUD) within East Asians as well as characterized potential moderating factors in these associations. METHODS For meta-analysis, 32 articles were selected that investigated ALDH2 (n = 17,755), ADH1B (n = 13,591) and ADH1C (n = 4,093) associations with AUD in East Asians. RESULTS AND CONCLUSIONS All three variants were associated with AUD across allelic and genotypic models: ALDH2, ORs = 0.25, P < 0.001; ADH1B, ORs = 0.22-0.49, P < 0.001; ADH1C, ORs = 0.26-0.46, P < 0.001. Composite analyses suggested genetic associations did not differ across ALDH2*2 and ADH1B*2, correcting for multiple comparisons. Moderation analyses suggested ADH1B was more strongly associated with AUD among samples with cases recruited from treatment than the community. Also, strength of ALDH2 and/or ADH1B associations varied with mean age and proportion of men in cases and controls. Findings support medium to large and unique associations of ALDH2, ADH1B, and ADH1C with AUD in East Asians. Results also identified novel methodological and sample characteristics that may modulate strength of these associations.
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Affiliation(s)
- Michelle J Zaso
- Department of Psychology, Syracuse University, 430 Huntington Hall, Syracuse, NY, USA
| | - Patricia A Goodhines
- Department of Psychology, Syracuse University, 430 Huntington Hall, Syracuse, NY, USA
| | - Tamara L Wall
- Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.,V.A. San Diego Health System, 3350 La Jolla Village Drive, San Diego, CA, USA
| | - Aesoon Park
- Department of Psychology, Syracuse University, 430 Huntington Hall, Syracuse, NY, USA
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46
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Huang PH, Hu CC, Chien CH, Chen LW, Chien RN, Lin YS, Chao M, Lin CL, Yeh CT. The Defective Allele of Aldehyde Dehydrogenase 2 Gene is Associated with Favorable Postoperative Prognosis in Hepatocellular Carcinoma. J Cancer 2019; 10:5735-5743. [PMID: 31737110 PMCID: PMC6843870 DOI: 10.7150/jca.33221] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 08/13/2019] [Indexed: 12/23/2022] Open
Abstract
Background: The Aldehyde dehydrogenase 2 (ALDH2) mutant genotypes contain an allele encoding defective ALDH2 with reduced efficacy of alcohol metabolism leading to accumulation of highly toxic and carcinogenic acetaldehyde. It can induce unpleasant "Asian flush syndrome" and associate with increased risk of cancers. However, to date, little is known about ALDH2 genotypes in relation to the postoperative prognosis of hepatocellular carcinoma (HCC). Methods: From 2002 to 2012, 419 HCC patients receiving surgical resection of HCC were enrolled for ALDH2-rs671 genotyping and outcome correlation. Results: Of the patients included, 202 were ALDH2-rs671 "GG" (wild type) and 217 were mutant (defective) "AA" + "GA" genotype. Kaplan-Meier analysis indicated that "GG" genotype significantly associated with shorter metastasis-free (P = 0.034) and overall (P = 0.005) survival, but not recurrence-free survival (P = 0.281). Univariate followed by multivariate Cox proportional hazard analysis showed that "GG" genotype was an independent clinical predictor for shorter time-to-distant metastasis (adjusted P = 0.019) and shorter overall survival (adjusted P = 0.001). Subgroup analysis showed that in patients with negative hepatitis B surface antigen, Edmonson's histology grade < 3, and aspartate transaminase > alanine transaminase, the ALDH2-rs671-GG genotype was associated with both shorter time-to-metastasis and shorter overall survival. Conclusions: HCC patients carrying a defective allele of ALDH2 had a favorable postoperative outcome.
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Affiliation(s)
- Po-Han Huang
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Chih Hu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Cheng-Hung Chien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Li-Wei Chen
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Rong-Nan Chien
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | | | - Mei Chao
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.,Division of Microbiology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
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47
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Zhang X, Geng X, Sun N, Li S, Li J, Wang S, Wang Q. There is no association between rs6296 and alcoholism: a meta-analysis. J Ethn Subst Abuse 2019; 20:366-378. [PMID: 31510870 DOI: 10.1080/15332640.2019.1657543] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Previous studies have reported controversial results about the association between rs6296 and alcoholism. Thus, a meta-analysis was performed to further explore this association. A comprehensive search was conducted to identify relevant case-control or cohort studies (up to December 1, 2017). A fixed- or random-effect model was selected as a pooling method depending on the heterogeneity among studies. The heterogeneity was measured by Q test and I2 statistic. The Harbord and Peters test was used to estimate publication bias. Fifteen English articles with 16 outcomes and 5,429 participants were included in this meta-analysis. A fixed-effect model was chosen, and the pooled result showed that rs6296 was not related to alcoholism (z = 1.93, p = .053). The Harbord and Peters test showed that there was no publication bias. This meta-analysis indicated that rs6296 may be not be significantly associated with alcoholism, which needs to be further confirmed by future research.
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Affiliation(s)
- Xueli Zhang
- Department of Histology and Embryology, Weifang Medical University, Shandong, China
| | - Xuefeng Geng
- Department of Epidemiology, Weifang Medical University, Shandong, China
| | - Na Sun
- Department of Health Statistics, Weifang Medical University, Shandong, China
| | - Suyun Li
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Shandong, China
| | - Jing Li
- Department of Environmental Health, Weifang Medical University, Shandong, China
| | - Suzhen Wang
- Department of Health Statistics, Weifang Medical University, Shandong, China
| | - Qiang Wang
- Department of Epidemiology, Weifang Medical University, Shandong, China
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Gelernter J, Sun N, Polimanti R, Pietrzak RH, Levey DF, Lu Q, Hu Y, Li B, Radhakrishnan K, Aslan M, Cheung KH, Li Y, Rajeevan N, Sayward F, Harrington K, Chen Q, Cho K, Honerlaw J, Pyarajan S, Lencz T, Quaden R, Shi Y, Hunter-Zinck H, Gaziano JM, Kranzler HR, Concato J, Zhao H, Stein MB. Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci. Biol Psychiatry 2019; 86:365-376. [PMID: 31151762 PMCID: PMC6919570 DOI: 10.1016/j.biopsych.2019.03.984] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 03/16/2019] [Accepted: 03/18/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.
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Affiliation(s)
- Joel Gelernter
- Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
| | - Ning Sun
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut
| | - Renato Polimanti
- Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Robert H Pietrzak
- Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Daniel F Levey
- Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Qiongshi Lu
- Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut
| | - Yiming Hu
- Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut
| | - Boyang Li
- Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut
| | - Krishnan Radhakrishnan
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut
| | - Mihaela Aslan
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Kei-Hoi Cheung
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Yuli Li
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut
| | - Nallakkandi Rajeevan
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut
| | - Fred Sayward
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut
| | - Kelly Harrington
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts
| | - Quan Chen
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut
| | - Kelly Cho
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jacqueline Honerlaw
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts
| | - Saiju Pyarajan
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Todd Lencz
- Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York; Department of Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York; Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, New York; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York
| | - Rachel Quaden
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts
| | - Yunling Shi
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts
| | - Haley Hunter-Zinck
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts
| | - J Michael Gaziano
- Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Henry R Kranzler
- Veterans Integrated Services Networks (VISN) 4 Mental Illness Research, Education and Clinical Center, Crescenz VA Medical Center, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - John Concato
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Hongyu Zhao
- Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut
| | - Murray B Stein
- Psychiatry Service, VA San Diego Healthcare System, San Diego, California; Department of Psychiatry, University of California San Diego, La Jolla, California.
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49
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Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. Alcohol use disorders. Lancet 2019; 394:781-792. [PMID: 31478502 DOI: 10.1016/s0140-6736(19)31775-1] [Citation(s) in RCA: 398] [Impact Index Per Article: 66.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/30/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022]
Abstract
Alcohol use disorders consist of disorders characterised by compulsive heavy alcohol use and loss of control over alcohol intake. Alcohol use disorders are some of the most prevalent mental disorders globally, especially in high-income and upper-middle-income countries; and are associated with high mortality and burden of disease, mainly due to medical consequences, such as liver cirrhosis or injury. Despite their high prevalence, alcohol use disorders are undertreated partly because of the high stigma associated with them, but also because of insufficient systematic screening in primary health care, although effective and cost-effective psychosocial and pharmacological interventions do exist. Primary health care should be responsible for most treatment, with routine screening for alcohol use, and the provision of a staggered treatment response, from brief advice to pharmacological treatment. Clinical interventions for these disorders should be embedded in a supportive environment, which can be bolstered by the creation of alcohol control policies aimed at reducing the overall level of consumption.
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Affiliation(s)
- Andre F Carvalho
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Markus Heilig
- Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | | | - Charlotte Probst
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Jürgen Rehm
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Clinical Psychology and Psychotherapy, and Center for Clinical Epidemiology and Longitudinal Studies, Technische Universität Dresden, Dresden, Germany; Department of International Health Projects, Institute for Leadership and Health Management, IM Sechenov First Moscow State Medical University, Moscow, Russia.
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50
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Rompala GR, Homanics GE. Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline. Alcohol Clin Exp Res 2019; 43:1032-1045. [PMID: 30908630 PMCID: PMC6551262 DOI: 10.1111/acer.14029] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 03/13/2019] [Indexed: 12/11/2022]
Abstract
While alcohol use disorder (AUD) is a highly heritable psychiatric disease, efforts to elucidate that heritability by examining genetic variation (e.g., single nucleotide polymorphisms) have been insufficient to fully account for familial AUD risk. Perhaps not coincidently, there has been a burgeoning interest in novel nongenomic mechanisms of inheritance (i.e., epigenetics) that are shaped in the male or female germ cells by significant lifetime experiences such as exposure to chronic stress, malnutrition, or drugs of abuse. While many epidemiological and preclinical studies have long pointed to a role for the parental preconception environment in offspring behavior, over the last decade many studies have implicated a causal relationship between the environmentally sensitive sperm epigenome and intergenerational phenotypes. This critical review will detail the heritable effects of alcohol and the potential role for epigenetics.
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Affiliation(s)
- Gregory R Rompala
- Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Gregg E Homanics
- Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School Medicine, Pittsburgh, Pennsylvania
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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