Alcohol dependence (AD) is a chronically relapsing disease and has various biological etiologies. Neither genetics nor neurobiology explains the pathogenesis of AD exclusively. AD is a multifactorial disease. This article reviews the genetic and biological aspects of AD. Many candidate genes and neurotransmitters play important roles in AD. Further studies are needed to elucidate the biological mechanisms of AD. Also the treatment of AD should be individualized according to the patients's biological characteristics.
Alcoholism* ; Biology* ; Genetics ; Neurobiology ; Neurotransmitter Agents ; Population Characteristics

BACKGROUNDAlcohol dependence (AD) is a serious and common public health problem. The identification of genes that contribute to the AD variation will improve our understanding of the genetic mechanism underlying this complex disease. Previous genome-wide association studies (GWAS) and candidate gene genetic association studies identified individual genes as candidates for alcohol phenotypes, but efforts to generate an integrated view of accumulative genetic variants and pathways under alcohol drinking are lacking.

METHODSWe applied enrichment gene set analysis to existing genetic association results to identify pertinent pathways to AD in this study. A total of 1 438 SNPs (P < 1.0 × 10(-3)) associated to alcohol drinking related traits have been collected from 31 studies (10 candidate gene association studies, 19 GWAS of SNPs, and 2 GWAS of copy number variants).

RESULTSAmong all of the KEGG pathways, the calcium signaling pathway (hsa04020) showed the most significant enrichment of associations (21 genes) to alcohol consumption phenotypes (P = 5.4 × 10(-5)). Furthermore, the calcium signaling pathway is the only pathway that turned out to be significant after multiple test adjustments, achieving Bonferroni P value of 0.8 × 10(-3) and FDR value of 0.6 × 10(-2), respectively. Interestingly, the calcium signaling pathway was previously found to be essential to regulate brain function, and genes in this pathway link to a depressive effect of alcohol consumption on the body.

CONCLUSIONSOur findings, together with previous biological evidence, suggest the importance of gene polymorphisms of calcium signaling pathway to AD susceptibility. Still, further investigations are warranted to uncover the role of this pathway in AD and related traits.

Alcoholism ; genetics ; Calcium Signaling ; genetics ; physiology ; Genetic Predisposition to Disease ; genetics ; Genome-Wide Association Study ; methods ; Humans ; Polymorphism, Single Nucleotide ; genetics

Alcoholism ; metabolism ; Animals ; Brain ; metabolism ; Chemokine CCL2 ; genetics ; metabolism ; Male ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, CCR2 ; genetics ; metabolism

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.
Adult ; Alcohol Dehydrogenase/*genetics ; Alcoholism/enzymology/genetics ; Aldehyde Dehydrogenase/*genetics ; Central Nervous System Depressants/pharmacokinetics ; Cytochrome P-450 CYP2E1/*genetics ; Ethanol/pharmacokinetics ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Human ; Korea ; Liver Cirrhosis, Alcoholic/enzymology/*genetics ; Male ; Middle Age ; *Polymorphism (Genetics)

BACKGROUND/AIMS: Genetic variations of ethanol-metabolizing enzymes can affect alcohol drinking behavior. The aims of this study were to investigate and compare the distributions of these genetic polymorphisms between a healthy control group and a heavy drinker group which included an alcoholic liver cirrhosis group. METHODS: Genotypes of ADH2, ALDH2, CYP2E1, and catalase were identified by polymerase chain reaction and restriction fragment length polymorphism. Genomic DNA was extracted from peripheral leukocytes in 42 healthy controls, 12 heavy drinkers, and 30 alcoholic liver cirrhosis patients. RESULTS: 1) The genotype frequencies of ALDH2 (1*1), ADH2 (1*1), CYP2E1 (c1c1), and catalase1 (TT) were 69%, 55%, 38%, and 12%, respectively in healthy Korean males. 2) There was a significant difference in the distribution of the genetic polymorphism of ALDH2 between the control group and heavy drinker group (12 heavy drinkers and 30 alcoholic liver cirrhosis patients). The genotype frequency of ALDH2 mutant, ALDH2 (1*2) and ALDH2 (2*2) in the heavy drinker group (12%) was significantly lower than that in the control group (30%). 3) We didn't find anyone with ALDH2 homozygote mutant (DD) in the heavy drinker group. 4) There was no significant difference in the distribution of genetic polymorphisms in ADH2, CYP2E1 and catalase1 between the two groups. CONCLUSIONS: These results suggest that the absence of ALDH2 mutant genotype is strongly related to heavy drinking behavior. We can not prove, however, any evidence that the polymorphisms of other ethanol-metabolizing enzymes are associated with the determination of alcohol-drinking behavior.
Adult ; Alcohol Dehydrogenase/*genetics ; Alcohol Drinking ; Alcoholism/enzymology/*genetics ; Aldehyde Dehydrogenase/*genetics ; Cytochrome P-450 CYP2E1/*genetics ; Ethanol/metabolism ; Humans ; Liver Cirrhosis, Alcoholic/enzymology/*genetics ; Male ; Middle Aged ; *Polymorphism, Genetic

Family, twin, and adoption studies have demonstrated that genes play an important role in the development of alcoholism. We investigated the association between alcoholism and the genetic polymorphisms of the GABA(A) receptor genes on chromosome 5q33-34 in Korean population. The genotype of the GABA(A) receptor gene polymorphisms were determined by performing polymerase chain reaction genotyping for 172 normal controls and 162 male alcoholics who are hospitalized in alcoholism treatment institute. We found a significant association between the genetic polymorphisms of the GABA(A) alpha1 and GABA(A) alpha6 receptor gene and alcoholism. The GG genotype of the GABA(A) alpha1 receptor gene was associated with the onset age of alcoholism and alcohol withdrawal symptoms, and a high score on the Korean version of the ADS. However, there was no association between the genetic polymorphisms of the GABA(A) beta2 and gamma2 receptor gene and alcoholisms. Our finding suggest that genetic polymorphisms of the GABA(A) alpha1 and GABA(A) alpha6 receptor gene may be associated with the development of alcoholism and that the GG genotype of the GABA(A) alpha1 receptor gene play an important role in the development of the early onset and the severe type of alcoholism.
Sequence Analysis, DNA ; Receptors, GABA-A/*genetics ; *Polymorphism, Genetic ; Models, Statistical ; Middle Aged ; Male ; Korea ; Humans ; *Genetic Predisposition to Disease ; DNA/metabolism ; *Chromosomes, Human, Pair 5 ; Alcoholism/*genetics ; Age of Onset ; Adult

Alcoholism ; epidemiology ; genetics ; Alleles ; Asian Continental Ancestry Group ; genetics ; China ; epidemiology ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Liver Diseases, Alcoholic ; epidemiology ; genetics ; Male ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Promoter Regions, Genetic ; genetics ; Tumor Necrosis Factor-alpha ; genetics

Alcoholism ; physiopathology ; prevention & control ; Animals ; Drugs, Chinese Herbal ; pharmacology ; Glucosides ; pharmacology ; Male ; Maze Learning ; drug effects ; Memory Disorders ; prevention & control ; Prefrontal Cortex ; metabolism ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; genetics ; metabolism ; Stilbenes ; pharmacology

Alcoholism ; drug therapy ; metabolism ; physiopathology ; Animals ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hippocampus ; metabolism ; Learning ; drug effects ; physiology ; Male ; Memory ; drug effects ; physiology ; Phytotherapy ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; genetics ; metabolism ; Superoxide Dismutase ; metabolism

Alcohol dependence is a chronic disorder that results from a variety of genetic, psychosocial, and environmental factors. Relapse prevention for alcohol dependence has traditionally involved psychosocial and psychotherapeutic interventions. Pharmacotherapy, however, in conjunction with behavioral therapy, is generating interest as another modality to prevent relapse and enhance abstinence. Naltrexone and acamprosate are at the forefront of the currently available pharmacological options. Naltrexone is an opioid receptor antagonist and is thought to reduce the rewarding effect of alcohol. Acamprosate normalizes the dysregulation of N-methyl-D-aspartate (NMDA)-mediated glutamatergic excitation that occurs in alcohol withdrawal and early abstinence.These different mechanisms of action and different target neurotransmitter systems may endow the two drugs with efficacy for different aspects of alcohol use behavior. Since not all patients seem to benefit from naltrexone and acamprosate, there are ongoing efforts to improve the treatment outcomes by examining the advantages of combined pharmacotherapy and exploring the variables that might predict the response of the medications. In addition, novel medications are being investigated to assess their efficacy in preventing relapse and increasing abstinence.
gamma-Aminobutyric Acid/metabolism ; Taurine/analogs & derivatives/therapeutic use ; Recurrence ; Receptors, Opioid, mu/genetics/metabolism ; Receptors, Opioid/antagonists & inhibitors ; Polymorphism, Genetic ; Neurons/metabolism ; Naltrexone/therapeutic use ; N-Methylaspartate/metabolism ; Models, Neurological ; Models, Biological ; Humans ; Glutamine/metabolism ; Disulfiram/therapeutic use ; Alcoholism/*drug therapy ; Alcohol Deterrents/*therapeutic use