Gene-environment interactions occur when different surroundings make it more or less likely for a particular trait or disorder to develop.

The concept of ‘alcogenic’ environments describes features, such as alcohol outlet density or marketing, which influence patterns of alcohol consumption.

A recent study, which analysed longitudinal data of 18–26-year-olds, has examined the link between genetic variation in alcohol problems and the number of alcohol outlets in a community.

The results from the study found that:

• There was evidence to suggest that the extent of genetic and environmental influences on alcohol problems varied with the density of alcohol outlets in the community.
• The heritability of alcohol problems for those residing in a neighbourhood with more than 10 on-premises outlets was 78% compared with 11% for those in a community with no on-premises outlets.

Overall the results suggest that in environments with fewer alcohol outlets and availability the genetic predisposition to develop problems is dampened. However, in environments where there is greater availability of alcohol the genetic predisposition is heightened.

The researchers suggest that people who are genetically predisposed to develop alcohol problems may be especially sensitive to the influence of alcohol outlet density in their community. This has potential implications for the design of prevention interventions.

Abstract

Rationale

Alcoholism is a primary, chronic relapsing disease of brain reward, motivation, memory, and related circuitry. It is characterized by an individual’s continued drinking despite negative consequences related to alcohol use, which is exemplified by alcohol use leading to clinically significant impairment or distress. Chronic alcohol consumption increases the expression of innate immune signaling molecules (ISMs) in the brain that alter cognitive processes and promote alcohol drinking.

Objectives

Unraveling the mechanisms of alcohol-induced neuroimmune gene induction is complicated by positive loops of multiple cytokines and other signaling molecules that converge on nuclear factor kappa-light-chain-enhancer of activated B cells and activator protein-1 leading to induction of additional neuroimmune signaling molecules that amplify and expand the expression of ISMs.

Results

Studies from our laboratory employing reverse transcription polymerase chain reaction (RT-PCR) to assess mRNA, immunohistochemistry and Western blot analysis to assess protein expression, and others suggest that ethanol increases brain neuroimmune gene and protein expression through two distinct mechanisms involving (1) systemic induction of innate immune molecules that are transported from blood to the brain and (2) the direct release of high-mobility group box 1 (HMGB1) from neurons in the brain. Released HMGB1 signals through multiple receptors, particularly Toll-like receptor (TLR) 4, that potentiate cytokine receptor responses leading to a hyperexcitable state that disrupts neuronal networks and increases excitotoxic neuronal death. Innate immune gene activation in brain is persistent, consistent with the chronic relapsing disease that is alcoholism. Expression of HMGB1, TLRs, and other ISMs is increased several-fold in the human orbital frontal cortex, and expression of these molecules is highly correlated with each other as well as lifetime alcohol consumption and age of drinking onset.

Conclusions

The persistent and cumulative nature of alcohol on HMGB1 and TLR gene induction support their involvement in alcohol-induced long-term changes in brain function and neurodegeneration.