A National Swedish Twin-Sibling Study of Alcohol Use Disorders.

The relationship between the genetic and environmental risk factors for alcohol use disorders (AUD) detected in Swedish medical, pharmacy, and criminal registries has not been hitherto examined. Prior twin studies have varied with regard to the detection of shared environmental effects and sex differences in the etiology of AUD. In this report, structural equation modeling in OpenMx was applied to (1) the three types of alcohol registration in a population-based sample of male-male twins and reared-together full and half siblings (total 208,810 pairs), and (2) AUD, as a single diagnosis, in male-male, female-female, and opposite-sex (OS) twins and reared-together full and half siblings (total 787,916 pairs). An independent pathway model fit best to the three forms of registration and indicated that between 70% and 92% of the genetic and 63% and 98% of the shared environmental effects were shared in common with the remainder unique to each form of AUD registration. Criminal registration had the largest proportion of unique genetic and environmental factors. The best fit model for AUD estimated the heritability to be 22% and 57%, respectively, in females and males. Both shared (12% vs. 6%) and special twin environment (29% vs. 2%) were substantially more important in females versus males. In conclusion, AUD ascertained from medical, pharmacy, and criminal Swedish registries largely share the same genetic and environmental risk factors. Large sex differences in the etiology of AUD were seen in this sample, with substantially stronger familial environmental and weaker genetic effects in females versus males.

An imbalance between VEGF and endostatin underlies impaired angiogenesis in gastric mucosa of aging rats.

Gastric mucosa of aging individuals exhibits increased susceptibility to injury and delayed healing. Our previous studies in young rats showed that healing of mucosal injury depends on and is critically dependent on VEGF and angiogenesis. Since angiogenesis in aging gastric mucosa has not been examined before, in this study we examined the extent to which angiogenesis is impaired in gastric mucosa of aging vs. young rats and determined the underlying mechanisms with a focus on mucosal expression of VEGF (proangiogenic factor) and endostatin (antiangiogenic factor). Aging rats had significantly impaired gastric angiogenesis by ~12-fold, 5-fold, 4-fold, and 3-fold, respectively (vs. young rats; all P < 0.001) at 24, 48, 72, and 120 h following ethanol-induced gastric injury and reduced and delayed healing of mucosal erosions. In gastric mucosa of aging (vs. young) rats at baseline, VEGF expression was significantly reduced, whereas endostatin levels were significantly increased (P < 0.05 and P < 0.01, respectively). In contrast to young rats, gastric mucosal VEGF levels did not increase following ethanol-induced injury in aging rats. MMP-9 enzyme activity was significantly higher in gastric mucosa of aging vs. young rats both at baseline (2.7-fold) and 24 h (3.8-fold) after ethanol injury (both P < 0.001). Since endostatin is generated from collagen XVIII by MMP-9, this finding can explain the mechanism of increased endostatin expression in aging gastric mucosa. The above findings demonstrate that reduced VEGF and increased endostatin result in the impaired angiogenesis and delayed injury healing in gastric mucosa of aging rats.

A novel SGCE gene mutation causing myoclonus dystonia in a family with an unusual phenotype.

BACKGROUND: Myoclonus dystonia is an autosomal dominant dystonia-plus syndrome, characterized by symptom variability within families. Most often is the myoclonus the most debilitating symptom, and many patients report myoclonus reduction after alcohol intake. In several families, mutations in the SGCE gene have been identified. METHOD: We report of a three-generation family with myoclonus dystonia displaying a varied phenotype and maternal imprinting. Additionally, this family displays some unusual clinical presentations including alcohol-induced dystonia in an adult man, which will be discussed. RESULTS: A novel mutation c.386T>C [p.I129T] was found within exon 3 of the SGCE gene in all three affected family members. In addition, two additional mutations [c.305G>A and IVS3+15G>A], judged to be polymorphisms in the SGCE gene, were found in two affected and one healthy family member. CONCLUSIONS: This report presents a novel mutation in the SGCE gene causing myoclonus dystonia and extends the phenotype of myoclonus dystonia to also include alcohol-induced dystonia.

The effects of MIR137HG genetic polymorphisms on the susceptibility of alcohol-induced osteonecrosis of the femoral head in a Chinese male population.

BACKGROUNDS: Osteonecrosis of the femoral head (ONFH) is one of the common and complicated diseases in the orthopedic clinic. Previous studies indicate that genetic factors play a crucial role in the occurrence of ONFH. This case-control study aimed to investigate the associations of MIR137HG genetic polymorphisms with the alcohol-induced ONFH risk. METHODS: A total of 731 participants were recruited to detect the effect of MIR137HG SNPs on the alcohol-induced ONFH risk in a Chinese male population. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations. Multifactor dimensionality reduction (MDR) was used to analyze the SNP-SNP interaction with the alcohol-induced ONFH risk. RESULTS: Our study showed that rs7549905 played a protective role in alcohol-induced ONFH risk (OR 0.57, p = 0.045). Stratified analysis indicated that rs9440302 was associated with an increased risk of patients aged >45 years (OR 2.00, p = 0.038), and rs7549905 showed a reduced risk in patients aged ≤ 45 years (OR 0.43, p = 0.023). In addition, we found that rs9440302 and rs7554283 exhibited a significantly increased susceptibility of III-IV grade alcohol-induced ONFH patients (OR 2.34, p = 0.003; OR 2.13, p = 0.011, respectively). We also observed that rs12138817 was related to an increased risk in patients with >21 months of course (OR 1.77, p = 0.043). Interestingly, rs17371457 showed a significant correlation with low-density lipoprotein-cholesterol (p = 0.040). CONCLUSION: Our study suggests that MIR137HG genetic variants are associated with the alcohol-induced ONFH susceptibility in a Chinese male population, which may give scientific evidence for exploring molecular mechanisms of the alcohol-induced ONFH.

GABRA2 and alcohol use disorders: no evidence of an association in an Italian case-control study.

BACKGROUND: Alcoholism is a major health and social issue, a highly frequent disease and a cause of premature death. It is also the most expensive addictive disorder being related to high morbidity and mortality, violence, accidents, and social and legal problems. It is a quantitative disorder, where the combined incidence of environmental and multiple genetic factors varies from 1 subject to another. Recent association studies have identified several genes as candidates for alcoholism, including GABAA receptor genes, due to their role in mediating several behavioral effects of alcohol, such as motor incoordination, anxiolysis, sedation, and withdrawal. The proposed association between the 3' half of the gene encoding the alpha-2 subunit of GABA receptor (3'-GABRA2) and alcohol use disorders (AUDs) has received several independent confirmations. METHODS: In this study, 10 single nucleotide polymorphisms (SNPs) of the 3'-GABRA2 gene, previously reported to be implicated in alcohol dependence, were used to evaluate the linkage between selected SNPs and AUDs in an Italian sample and to compare findings with those of previous studies. RESULTS: No evidence of an association was found at the allele, genotype, haplotype, or diplotype levels between the 3'-GABRA2 polymorphisms investigated and alcoholism in 149 Italian alcoholics (98 alcohol dependents and 51 alcohol abusers) and 278 controls. CONCLUSIONS: Despite previous reports, we did not find an association between AUDs and 3'-GABRA2 polymorphisms. This is probably due to the minimal comorbidity of our Italian sample suggesting that this gene is implicated in polysubstance dependence rather than in alcoholism alone.

Prediction of deleterious non-synonymous single nucleotide polymorphisms of genes related to ethanol-induced toxicity.

Non-synonymous single nucleotide polymorphisms (nsSNPs) that cause amino acid changes are believed to have a large impact on protein function. It is important to distinguish those deleterious nsSNPs that affect protein function from those that are functionally neutral. Ethanol causes organ toxicity with involvement of a number of genes encoding functional proteins. We have identified 1509 alcohol-responsive genes after a systemic search of previous human studies, with 580 being up-regulated and 847 down-regulated. The samples for gene expression analysis of ethanol exposure are from the brain, liver, and cultured human cells. These genes mainly encode proteins involved in nucleic acid binding, transcription, and signal transduction. These ethanol-responsive genes also correlated with other biological pathways, such as angiogenesis, integrin signalling pathway, and inflammation. The number of nsSNPs in the 1509 validated alcohol-responsive genes was 9207. Using the PolyPhen and SIFT algorithms, 41.5% nsSNPs were predicted to be deleterious. These findings provide some insights into the molecular targets of ethanol-induced toxicity and how genetic mutation would affect the toxicity phenotype. A better understanding of the relationship between genotype and phenotype of nsSNPs of ethanol-responsive genes will provide useful hints for further research on alcohol-induced toxicity and potential therapy.

Fingerprint profile of alcohol-associated heart failure in human hearts.

BACKGROUND: Excessive alcohol consumption is recognized as a cause of left ventricular dysfunction and leads often to alcohol-induced heart failure. It is thought that 36% of all cases of dilated cardiomyopathy are due to excessive alcohol intake. In addition, since chronic alcohol-consumption is a social behavior that is not always clearly self-reported clinically, it has been difficult to diagnose alcohol-induced heart failure versus heart failure due to idiopathic dilated cardiomyopathy (IDCM). Interestingly, both diseases are associated with left ventricular dysfunction and congestive heart failure. METHODS: We have created a human heart failure cDNA array for IDCM from nonfailing and failing human hearts. The array contains 1,143 heart specific oligonucleotide probes. This array was used to screen RNA samples from transplant recipients and organ donors with alcohol-related heart failure. RESULTS: Our study shows that alcohol-induced heart failure has a "specific fingerprint" profile of de-regulated genes. This profile can differentiate patients with pure alcohol-induced heart failure from patients with heart failure from IDCM with alcohol as a complicating or contributing factor. Furthermore, the pattern of gene de-regulation suggests a pivotal role for changes in matrix, cytoskeletal, and structural proteins in the development of clinical heart failure resulting from excessive alcohol consumption. CONCLUSIONS: We report for the first time a genomic "fingerprint" profile of de-regulated genes associated with human alcohol-induced heart failure. We conclude that the pathogenesis of alcohol-induced heart failure in humans is likely related to changes in architectural (e.g. cytoskeletal), matrix, and/or structural proteins. The reversibility of the disease upon cessation of alcohol consumption makes this a likely pathogenetic mechanism. Nevertheless, there is a point at which extracellular as well as cellular changes result in irreversible heart failure.

Ethanol teratogenesis in Japanese medaka: effects at the cellular level.

The adverse effects of alcohol on the developing humans represent a spectrum of structural and neurobehavioral abnormalities, most appropriately termed as fetal alcohol spectrum disorder (FASD). The mechanism by which ethanol induces FASD is unknown. Human studies of FASD are very limited due to ethical constraints; however, several animal models from nematodes to mammals are utilized to understand the molecular mechanism of this disorder. We have used Japanese medaka (Oryzias latipes) embryo-larval development as a unique non-mammalian model to study the molecular mechanism of FASD. Fertilized medaka eggs were exposed to ethanol (0-400 mM) for 48 h post fertilization (hpf) and then maintained in regular embryo rearing medium without ethanol. Viable embryos were harvested on 0, 2, 4 and 6 day post fertilization (dpf) and analyzed for DNA, RNA and protein contents of the embryos. By applying semi-quantitative RT-PCR (rRT-PCR) and quantitative real-time RT-PCR (qRT-PCR), RNA samples were further analyzed for seven transcription factors, emx2, en2, iro3, otx2, shh, wnt1 and zic5 which are expressed in the neural tube of medaka embryo during early phase of development. RNA and protein contents of the embryos were significantly reduced by ethanol at 400 mM dose on 4 and 6 dpf compared to the control (no ethanol), and 100 mM ethanol treated embryos. However, significant reduction of DNA was observed only in 4 dpf embryos. Total protein contents of yolk remained unaltered after ethanol treatment. Expression pattern of emx2, en2, iro3, otx2, shh, wnt1, and zic5 mRNAs were found to be developmentally regulated, however, remained unaltered after ethanol treatment. It is therefore concluded that alteration of nucleic acid and protein contents of medaka embryo by ethanol could be used as an indicator of embryonic growth retardation which might be the result of disruption of specific gene function during development.

Etomidate and propofol-hyposensitive GABAA receptor beta3(N265M) mice show little changes in acute alcohol sensitivity but enhanced tolerance and withdrawal.

Gamma-aminobutyric acid-A (GABAA) receptors are ligand-gated ion channels comprised of subunits from several classes (alpha, beta, gamma, delta). Recent studies have clearly demonstrated that the functional properties of GABAA receptors are altered following chronic ethanol administration that could provide the molecular basis for the previously proposed role of these receptors in ethanol tolerance and dependence. Because the subunit composition of GABAA receptors determines receptor pharmacology, the present study was devoted to assess if the behavioral sensitivity after acute and chronic ethanol exposure depends on beta3-containing GABAA receptors. In the present study, we used knock-in mice harboring a point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABAA receptor in order to study acute and chronic behavioral effects of ethanol. More specifically, we tested tolerance to loss of righting reflex (LORR) and the development of withdrawal signs after chronic ethanol exposure using ethanol vapor chambers. Our results show that the beta3(N265M) mutation does not play a major modulatory role of acute ethanol-induced LORR. However, following repeated LORR testing, enhanced tolerance to the intoxicating effects of ethanol was observed--a finding which was unrelated to the pharmacokinetics of ethanol as both genotypes had the same blood alcohol concentrations following repeated LORR testing. In addition, following chronic alcohol vapor exposure, mouse mutants displayed increased handling-induced convulsions during withdrawal. The results of the present study suggest that the alcohol effects abolished by the beta3(N265M) mutation do not play a dominant role in acute alcohol intoxication but influence ethanol tolerance and withdrawal.

Molecular and cellular events in alcohol-induced muscle disease.

Alcohol consumption induces a dose-dependent noxious effect on skeletal muscle, leading to progressive functional and structural damage of myocytes, with concomitant reductions in lean body mass. Nearly half of high-dose chronic alcohol consumers develop alcoholic skeletal myopathy. The pathogenic mechanisms that lie between alcohol intake and loss of muscle tissue involve multiple pathways, making the elucidation of the disease somewhat difficult. This review discusses the recent advances in basic and clinical research on the molecular and cellular events involved in the development of alcohol-induced muscle disease. The main areas of recent research interest on this field are as follows: (i) molecular mechanisms in alcohol exposed muscle in the rat model; (ii) gene expression changes in alcohol exposed muscle; (iii) the role of trace elements and oxidative stress in alcoholic myopathy; and (iv) the role of apoptosis and preapoptotic pathways in alcoholic myopathy. These aforementioned areas are crucial in understanding the pathogenesis of this disease. For example, there is overwhelming evidence that both chronic alcohol ingestion and acute alcohol intoxication impair the rate of protein synthesis of myofibrillar proteins, in particular, under both postabsorptive and postprandial conditions. Perturbations in gene expression are contributory factors to the development of alcoholic myopathy, as ethanol-induced alterations are detected in over 400 genes and the protein profile (i.e., the proteome) of muscle is also affected. There is supportive evidence that oxidative damage is involved in the pathogenesis of alcoholic myopathy. Increased lipid peroxidation is related to muscle fibre atrophy, and reduced serum levels of some antioxidants may be related to loss of muscle mass and muscle strength. Finally, ethanol induces skeletal muscle apoptosis and increases both pro- and antiapoptotic regulatory mechanisms.

Increased anxiety and other similarities in temperament of alcoholics with and without antisocial personality disorder across three diverse populations.

According to Cloninger's model, type I alcoholics are thought to be innately vulnerable to anxiety and depression. In contrast, type II alcoholics are thought to have increased likelihood of antisocial personality disorder (ASPD) and reduced anxiety. However, allostatic activations of stress, anxiety, and dysphoria may be a common thread in alcohol use disorders (AUDs). Our aim was to find commonalities and differences in temperament of alcoholics with and without ASPD in three diverse populations. By sib-sib comparisons, we also evaluated the extent to which the temperament traits were moderated by familial factors including inheritance. We compared harm avoidance (HA), novelty seeking (NS), and reward dependence (RD) in alcoholics with ASPD, alcoholics without ASPD, and controls. Correlations for each temperament dimension were evaluated in pairs of siblings concordant and discordant for AUD. Participants were derived from three independent populations: Finnish Caucasians (N=453, men=100%, including a sample of alcoholic criminals), a Plains American Indian community sample (N=378; men=42%), and a subset of the familial and predominantly Caucasian Collaborative Study on the Genetics of Alcoholism (COGA) sample (N=967, men=47%). In all the three populations, both alcoholics with and without ASPD were higher in HA than controls. The increase of HA among alcoholics as compared to controls ranged from 54% to 12%. In two populations (COGA and Finns), NS was highest in alcoholics with ASPD, intermediate in alcoholics without ASPD, and lowest in controls. HA levels were correlated in sib-pairs concordant (either affected or unaffected) for AUD but not in discordant pairs. In conclusions, despite cultural diversity and different modes of ascertainment we found a consistent pattern of elevated HA in all groups of alcoholics, including alcoholics with ASPD. Even in alcoholics with long-term exposure to the anxiogenic effects of repeated cycles of alcohol withdrawal, genetic and other familial influences seem to play a role in moderating anxiety.

DNA co-methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders.

DNA methylome alterations in the prefrontal cortex (PFC) may contribute to risk for alcohol use disorders (AUDs). We examined postmortem PFC DNA methylomes of 16 male and seven female pairs of AUD and control subjects using Illumina's HumanMethylation450 BeadChip assays. In male AUD subjects, 1,812 CpGs (1,099 genes) were differentially methylated (9.5 × 10(-9) ≤ Pnominal ≤ 7.2 × 10(-4), q < 0.05). In females, no CpGs were associated with AUDs after multiple testing correction (q > 0.05). Twenty-one AUD-associated co-methylation modules were identified in males by co-methylation analysis. The 1,812 CpGs were over-presented by two AUD-associated co-methylation modules (Mturquoise: 1,048 CpGs/683 genes; Mblue: 429 CpGs/304 genes) (Phyper ≤ 0.001). Biological processes enriched for genes in these two modules included neural development and transcriptional regulation. Genes mapped by CpGs in these two modules were enriched in genome-wide association study-identified genes with variants associated with four substance dependence phenotypes or five psychiatric disorders. Additionally, 106 of the 1,812 CpGs were mapped to 93 genes (e.g., AUD-associated genes GRIK3, GRIN2C, and GABRA1) with differential expression in postmortem PFC of male AUD subjects. Our study demonstrates that DNA methylation alterations in the PFC are associated with (and might result in) increased risk of AUDs, and there was a complex DNA methylation-gene expression relationship.

Selective breeding, quantitative trait locus analysis, and gene arrays identify candidate genes for complex drug-related behaviors.

Acute functional tolerance to ethanol develops during a single exposure to ethanol; it has been suggested to be a predisposing factor for the development of ethanol dependence. Genetic determinants of acute functional tolerance, as well as of ethanol dependence, have been clearly demonstrated. We describe a novel approach that uses a combination of selective breeding (to segregate genes contributing to the phenotype of interest, i.e., acute functional tolerance to the incoordinating effect of ethanol), quantitative trait locus analysis (to define chromosomal regions associated with acute functional tolerance), and DNA microarray technology (to identify differentially expressed genes in the brains of the selected lines of mice) to identify candidate genes for the complex phenotype of ethanol tolerance. The results indicate the importance of a signal transduction cascade that involves the glutamate receptor delta2 protein, the Ephrin B3 ligand, and the NMDA receptor, as well as a transcriptional regulatory protein that may be induced by activation of the NMDA receptor (zinc finger protein 179) and a protein that can modulate downstream responses to NMDA receptor activation (peroxiredoxin), in mediating acute tolerance to the incoordinating effect of ethanol.

Alcohol withdrawal severity in inbred mouse (Mus musculus) strains.

Male mice (Mus musculus) from 15 standard inbred strains were exposed to a nearly constant concentration of ethanol (EtOH) vapor for 72 hr, averaging 1.59 +/- 0.03 mg EtOH/mL blood at withdrawal. EtOH- and air-exposed groups were tested hourly for handling-induced convulsions for 10 hr and at Hours 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of control values), and by design these differences were independent of strain differences in EtOH metabolism. Correlation of strain mean withdrawal severity with other responses to EtOH supported previously reported genetic relationships of high EtOH withdrawal with low drinking, high conditioned taste aversion, low tolerance to EtOH-induced hypothermia, and high stimulated activity after low-dose EtOH. Also supported were the positive genetic correlations among EtOH, barbiturate, and benzodiazepine withdrawal. Sensitivity of naive mice to several chemical convulsant-induced seizures was also correlated with EtOH withdrawal.

Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology.

RATIONALE: Norepinephrine (NE) is a key neurotransmitter in the central and peripheral nervous systems. Dopamine beta-hydroxylase (DbetaH) catalyzes the synthesis of NE from dopamine (DA) and occurs in the plasma as a stable heritable trait. Studies of this trait have been useful in psychiatric and neurological research. OBJECTIVE: To selectively and critically review the literature on plasma DbetaH, and on recent progress understanding the molecular genetic basis for its inheritance. Based on this review, directions for future research in psychiatry and neurology will be suggested. METHODS: We selectively review the literature on the biochemical and molecular genetics of plasma DbetaH activity, as well as research on plasma and cerebrospinal fluid (CSF) DbetaH in psychiatric and neurological disorders. RESULTS: Strong evidence implicates DBH, the structural locus encoding DbetaH enzyme, as the major quantitative trait locus influencing plasma DbetaH activity, with one single nucleotide polymorphism (SNP) accounting for up to 50% of the variance. Mutations at DBH appear to be responsible for the rare syndrome of DbetaH deficiency. Some biochemical and genetic studies suggest associations between low plasma or CSF DbetaH and psychotic symptoms in several psychiatric disorders. Studies combining genotyping at DBH with biochemical measurement of plasma DbetaH have proven useful in studies of schizophrenia, cocaine-induced paranoia (CIP), depression, attention deficit hyperactivity disorder, and alcoholism. Such studies may also elucidate the contribution of noradrenergic dysfunction to a variety of symptoms in Parkinson's disease and other degenerative neurological disorders. CONCLUSIONS: A model is proposed, in which lower levels of DbetaH protein may lead to elevated ratios of DA to NE. This model may explain associations between lower plasma DbetaH activity and vulnerability to psychotic symptoms. Genotype-controlled analysis of plasma DbetaH holds promise for promoting further progress in research on psychiatric and neurological disorders.

Relation of attachment style to family history of alcoholism and alcohol use disorders in early adulthood.

The present study examined the association between paternal alcoholism and attachment style in early adulthood and sought to determine whether attachment style might, at least partially, mediate intergenerational risk for alcoholism. The current report focuses on the cross-sectional relation between family history (FH) of alcoholism, attachment styles, and alcohol use disorders (AUD) when cohort members were, on average, 29 years old (N = 369; 46% male; 51% FH+). Results indicated that FH+ participants were more likely to have insecure attachment, characterized by fearful-avoidant and dismissed-avoidant styles. Additionally, fearful-avoidant and dismissed-avoidant attachment styles were related to the presence of an AUD even after controlling for sex and FH (P < 0.05). There was little evidence, however, that attachment style mediated the relation between paternal alcoholism and AUD in offspring; the FH-AUD association was only negligibly reduced when the effect of attachment style was controlled. Our findings suggest that insecure attachment style is a risk factor for AUD, independent of familial risk for alcoholism.

Patterns of drug-related disorders in a prospective study of men chosen for their family history of alcoholism.

OBJECTIVE: Alcohol use disorders (AUDs) and abuse or dependence on illicit substances often co-exist. Most studies evaluating these phenomena have focused on less well-educated individuals, using cross-sectional designs. This study controls for several factors that might contribute to a propensity toward both alcohol and substance-related conditions in a prospective follow-up of middle-class men. METHOD: The subjects (N = 249) were white sons of alcoholics and controls, followed for 20 years using structured interviews. They were evaluated at baseline and again 10, 15 and 20 years later. RESULTS: One in five subjects developed an illicit substance-related disorder by the 20-year follow-up, most commonly abuse or dependence on cannabinoids and/or stimulants. The men with these diagnoses were more likely to be recent smokers, to also fulfill criteria for alcoholism and to have a family history of a stimulant use disorder. They were not more likely to have family histories of alcoholism, did not have a lower response to alcohol at age 20 and had no enhanced risk for independent psychiatric disorders, although they did have relatives with manic depressive disease. CONCLUSIONS: Disorders related to illicit substances were common in this well-educated, highly functional population. Substance-related comorbidity with alcoholism did not seem to reflect several factors known to predict AUDs (e.g., family history of alcoholism and a low response to alcohol). The diagnostic overlap between AUDs and illicit substance-related disorders might reflect concomitant family histories of alcoholism and substance-related conditions and, perhaps, family histories of manic depressive disease.

Genetic polymorphisms and response to medications for alcohol use disorders: a systematic review and meta-analysis.

AIM: To assess whether response to medications for alcohol use disorders varies by genotype. METHODS: Systematic review and meta-analysis. RESULTS: We found no studies that assessed the clinical utility of genotype-guided dosing strategies or genotype-guided medication selection, and none randomized by genotype. All included studies assessed the association between genotype and response to medication. Of 15 included studies, eight (n = 1365 participants) assessed variation in naltrexone response and polymorphisms of OPRM1. Our meta-analyses for return to heavy drinking found no significant difference between A allele homozygotes and those with at least one G allele, both without (risk difference: 0.26; 95% CI: -0.01-0.53; n = 174) and with inclusion of studies rated as high or unclear risk of bias (risk difference: 0.14; 95% CI: -0.03-0.3; n = 382). For all other polymorphism-medication pairs, we found just one eligible study. CONCLUSION: Estimates of effect for return to heavy drinking suggest it is possible that patients with at least one G allele of A118G polymorphism of OPRM1 might be more likely to respond to naltrexone, but confidence intervals were wide; additional studies are needed to improve confidence in the estimates.

MALAT-1, a non protein-coding RNA is upregulated in the cerebellum, hippocampus and brain stem of human alcoholics.

Chronic alcohol intake induces neurochemical adaptative changes in the brain characterised by altered gene expression. A role for non-coding RNAs in alcoholism is beginning to emerge. PCR-differential display using total RNA extracted from brain material of human alcoholics and control cases identified a cDNA fragment corresponding to a section of a known non protein-coding RNA (ncRNA), MALAT-1, (also known as NEAT2). Comparison of mRNA levels of MALAT-1 was performed by northern and dot blot experiments using different regions of brain from human alcoholics and rats chronically treated with ethanol vapours and following withdrawal. A massive increase of MALAT-1 transcripts was detected in cerebellum of human alcoholics and increases were also noted in hippocampus and brain stem, while no significant increase of MALAT-1 expression was noted in frontal or motor cortices. In the rat no significant difference of MALAT-1 ortholog mRNA could be detected in cerebellum. In addition, similarly to humans, no significant increase of MALAT-1 expression was detected in cortex of alcohol-treated rats, however, after 24 h alcohol withdrawal, a significant upregulation of MALAT-1 expression was observed in rat cortex. MALAT-1 is upregulated in specific regions of the human alcoholic brain and following alcohol withdrawal in the rat. As MALAT-1 regulates RNA processing, this suggests that alcohol-induced upregulation of MALAT-1 represents an important novel mechanism for alcohol actions in the CNS.

Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and alcohol-induced medical diseases.

BACKGROUND: The alcohol dehydrogenase 1B gene (ADH1B) is hypothesized to affect predisposition to alcohol dependence (AD) and abuse. A variant of the ADH1B gene (rs1229984 or Arg48His; previously referred to as Arg [*1] and His [*1]) has been reported to be associated with reduced rates of alcohol and drug dependence. Different studies have produced inconclusive results regarding association between rs1229984 (or rs2066702) and substance dependence. METHODS: Using the cumulative association study literature from the past 21 years from both English- and Chinese-language publications, this meta-analysis seeks to clarify the contradictory findings and to examine whether the aggregate data provide new evidence of significant association. RESULTS: The results, based on a large sample size (9638 cases and 9517 controls), suggested strong associations with alcohol dependence and abuse as well as alcohol-induced liver diseases, with an allelic (Arg vs. His) p value being 1 × 10(-36) and odds ratio (OR) (95% confidence intervals [CI]) 2.06 (1.84-2.31) under the random effects model. The dominant and recessive models produced larger ORs of 2.17 and 3.05, respectively. When more stringent criteria and subgroup analyses were imposed, the associations remained consistent and were strongest in various Asian groups (allelic p = 7 × 10(-42) and OR (95% CI) = 2.24 [1.99-2.51] with ORs of 2.16 and 4.11 for dominant and recessive models, respectively). CONCLUSIONS: Our findings provide further strong evidence for the involvement of the ADH1B gene in the pathogenesis of alcohol dependence and abuse as well as for some alcohol-induced medical diseases in the multiple ethnic populations--in particular, certain Asian populations.