Investigating the effects of genetic variability in mir-146a and its expression in the brain of human alcoholics

Abstract

Chronic use of alcohol leads to progressive changes in the human brain, which causes behavioral changes (Li, 2008) and dependence (Kalivas and O'Brien, 2008). MiRNAs act as crucial regulators and perform essential roles in Toll-like receptor (TLR) signalling pathways during neuroinflammation (Newton and Dixit, 2012), and in the brain of alcoholics, there is a differential expression of certain microRNAs (miRNAs). Association studies have reported that genetic variants in miRNAs can make an individual more susceptible to alcoholism (Kohnke, 2008). A single nucleotide polymorphism (SNP) in the miR-146a gene has been associated previously with alcohol use disorder (AUD) and is suggested to affect downstream regulatory pathways (Novo-Veleiro et al., 2014). Studies have also suggested that miRNAs that are affected by alcohol consumption may function in a homeostatic manner to decrease alcohol consumption (Most et al., 2019). The current study was performed to investigate the association of the two SNPs, rs2910164 and rs57095329, with alcohol misuse in a Caucasian population of European descent. This study showed that neither rs2910164 nor rs57095329 is associated with alcohol misuse, nor does it affect the expression of miR-146a in the frontal cortex or Interleukin-1 Receptor-Associated Kinase 1 (IRAK1) frontal and motor cortices. However, rs57095329 decreases TNF Receptor-Associated Factor 6 (TRAF6) expression in the frontal cortex but not in the motor cortex. The expression of IRAK1 was significantly different between the females and the males. Moreover, the expression of miR-146a was down-regulated in the alcoholics and changes were significant in the female population in comparison to the male population. Regional differences were also observed, whereby the expression of IRAK1 and TRAF6 was higher in the motor cortex compared with the frontal cortex. These results suggest that long term alcohol abuse leads to changes in miR-146a expression in the frontal cortex. Because IRAK1 and TRAF6 expression was not significantly different in alcoholics, there may be an apparent response to adaption due to increased exposure of alcohol to recover and reinstate homeostasis (Nunez et al., 2013). Elucidation of the mechanisms behind miR-146a regulation may provide deeper understanding of its role in alcohol induced neuroinflammation and propose therapeutic options in the treatment of alcohol misuse.