Resumo

DIAZ-ANZALDUA, Adriana; DIAZ-MARTINEZ, Alejandro  e  DIAZ-MARTINEZ, Leonila Rosa. The complex interplay of genetics, epigenetics, and environment in the predisposition to alcohol dependence. Salud Ment [online]. 2011, vol.34, n.2, pp.157-166. ISSN 0185-3325.

Alcohol dependence is a major global problem, associated with lower quality of physical and mental health, higher mortality and an enormous familial and social cost. Prevention strategies and treatment of this condition are therefore crucial. Success of psychosocial programs and pharmacological treatments has been frequently reported, but a better understanding of the etiology of this chronic disease is needed. For this purpose, the identification of associated factors in different populations is of great significance. It has been clearly demonstrated by twin and adoption studies and supported by animal models that both genetic and environmental components play a substancial role in alcohol dependence. Heritabil ity estimates range from 40 to 60%, depending on the specific analyzed sample. Several coexisting genetic variants in each affected individual, rather than a single gene transmitted in a Mendelian manner, may be the rule in alcohol dependence. Similarly, many environmental factors can increase susceptibility, and because of their diversity, they do not have to be the same in every affected person. Environmental contribution may be linked to epigenetics, which refers to chemical processes that can modify gene activity without changing the sequence of DNA. In humans, the most stable epigenetic process is the union of a methyl group (one carbon atom surrounded by three hydrogen atoms) to cytosines in DNA. Other epigenetic mechanisms are modifications to nuclear proteins called histones, which alter the way DNA is packed. Moreover, non-protein coding RNAs such as microRNAs have been associated with the development of alcohol dependence. MicroRNAs could work as epigenetic intermediaries that allow ethanol to affect complex and divergent developmental mechanisms, which is added to the effect of DNA methylation, histone acetylation, and other epigenetic modifications. Most reasearch points to an association between alcohol dependence and genes related with alcohol metabolism, with neurotransmission of dopamine, GABA, serotonin, glutamate, endogenous opioids, and cannabinoids, signal transduction within the mesolimbic dopamine reward system, and stress response system, among others. During pregnancy, there are several non-genetic factors that may have an important impact on vulnerability to alcohol dependence. Given that the Central Nervous System is developing throughout the entire pregnancy and that alcohol consumed by the mother can reach the fetus through the placental barrier, the brain of a baby is always vulnerable to harm caused by alcohol exposure. Children born to alcoholic mothers may inherit genetic susceptibility variants but at the same time they may be exposed to early effects of ethanol. Heavy alcohol exposure during pregnancy has been associated with mental retardation, epilepsy, attention deficit/ hyperactivity disorder, learning disabilities, and later on with substance abuse, anxiety, personality, affective and psychotic disorders, as well as with engagement in antisocial behaviors and school or work problems. Furthermore, it has been shown that animals exposed to prenatal stress exhibit persisting modifications related to dopamine and glutamate transmission in limbic structures associated with dependence to alcohol and other substances. These alterations may later contribute to increase motivation to drink, to use large amounts of drugs of abuse or to relapse after periods of drug withdrawal. It was shown that after exposure to prenatal stress, male mice consumed more ethanol during alcohol reinforcement in adulthood. In addition, it has been well documented that affective disorders are associated with alcohol dependence. A recent meta-analysis including 54 studies that together involved more than 40749 individuals, confirmed that the 5-HTTLPR polymorphism at the promoter of the serotonin transporter gene moderates the association between stress and depression, where the short allele is related with an increased risk for depression under stress (p = 0.00002). A strong association was detected when the stressful factor was childhood maltreatment (p = 0.00007). Childhood maltreatment, including neglect as well as physical and sexual abuse, is associated with developmental difficulties, low social competence and self-esteem, and it is an important risk factor for binge drinking in adolescence and alcohol dependence in adulthood. Childhood maltreatment may interact with factors such as variants of the monoamine oxidase-A and catechol-o-methyltransferase gene. Adolescence is a critical period for initiation of alcohol intake, experimentation, and establishment of regular drinking patterns. Substance use at this age is considered a risk factor for the development of later alcohol and other drug-related problems, as well as for externalizing disorders such as antisocial personality disorder. Alcohol use initiation is affected by environmental factors such as ethanol availability, parental attitudes, and peer pressure. It has been reported that heavy drinking during adolescence can have a negative impact on brain development. Moreover, dopaminergic and GABAergic systems undergo important changes during adolescence, and they can be affected by alcohol intake. Dopamine is implicated in the rewarding effects of ethanol, and GABA in its sedating effects and development of tolerance. The way an adult copes with environmental challenges is notably influenced by early life experiences and by the familial environment he or she had as an infant, which affects neurodevelopmental behavior. While environmental factors tend to have a crucial role in drinking habits in adolescence, adultood may be characterized by a weaker effect of environment and a higher effect of genetic components. It is probable that a complex set of gene-environment interactions determine the risk to alcohol dependence. Environmental factors that may affect this vulnerability appear at different stages from pregnancy to adulthood. These interactions are mediated by DNA methylation, histone modifications, protein complexes and non-protein-coding RNAs such as microRNAs.

Palavras-chave : Alcohol dependence; complex traits; gene-environment interaction; ethanol; alcoholism; epigenetics and alcohol; alcohol abuse in adolescence.

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