Genetic factors account for approximately 50 percent of the risk of alcohol dependence (Schuckit 2009). Multiple genes linked to innate immune function also have been linked to the risk for alcoholism (see figure 3). DNA variations (i.e., polymorphisms) at specific locations on the chromosomes result in gene variants (i.e., alleles) that differ in their function or activity and thereby may increase or reduce the risk of alcoholism. For example, polymorphisms in the gene encoding an enzyme called CYP2E1, which is involved in ethanol metabolism, have been associated with the risk for alcoholism (Webb et al. 2010). In the body, CYP2E1 is highly expressed in monocyte-like cells; ethanol metabolism by CYP2E1 leads to the activation of these cells. Specifically, CYP2E1-mediated ethanol metabolism causes an increased production of highly reactive molecules called reactive oxygen species (ROS) within the monocytes that activate proinflammatory NF-κB responses (Cao et al. 2005) (see figure 3). In the brain, ethanol exposure leads to increased CYP2E1 expression, particularly in astrocytes (Montoliu et al. 1994, 1995), which likely contributes to astrocyte activation of NF-κB transcription during chronic alcohol exposure.
