Finally, while some human studies have revealed a potential role for KOR gene (OPRK1) polymorphism in risk for and/or treatment of ethanol dependence (Ashenhurst et al., 2012; Xuei et al., 2006; Zhang et al., 2008), other studies have produced contradictory findings (Arias et al., 2008; Gelernter et al., 2007). Variations in the prodynorphin gene have also been associated with negative craving for alcohol (i.e., seeking alcohol for relief from a negative emotional state) and alcohol dependence (Karpyak et al., 2013). DNA methylation (associated with reduced gene expression) in the prodynorphin gene was increased in alcoholics relative to control subjects in cortex and blood cells (Taqi et al., 2011; D’Addario et al., 2017). Future work using animal models may be valuable in clarifying whether allelic variants of OPRK1 or epigenetic factors (e.g., differential methylation of the prodynorphin gene) significantly contribute to risk for alcohol use disorder (AUD) and/or treatment responsiveness.
