Prediction of deleterious non-synonymous single nucleotide polymorphisms of genes related to ethanol-induced toxicity

Abstract

Non-synonymous single nucleotide polymorphisms (nsSNPs) that cause amino acid changes are believed to have a large impact on protein function. It is important to distinguish those deleterious nsSNPs that affect protein function from those that are functionally neutral. Ethanol causes organ toxicity with involvement of a number of genes encoding functional proteins. We have identified 1509 alcohol-responsive genes after a systemic search of previous human studies, with 580 being up-regulated and 847 down-regulated. The samples for gene expression analysis of ethanol exposure are from the brain, liver, and cultured human cells. These genes mainly encode proteins involved in nucleic acid binding, transcription, and signal transduction. These ethanol-responsive genes also correlated with other biological pathways, such as angiogenesis, integrin signalling pathway, and inflammation. The number of nsSNPs in the 1509 validated alcohol-responsive genes was 9207. Using the PolyPhen and SIFT algorithms, 41.5% nsSNPs were predicted to be deleterious. These findings provide some insights into the molecular targets of ethanol-induced toxicity and how genetic mutation would affect the toxicity phenotype. A better understanding of the relationship between genotype and phenotype of nsSNPs of ethanol-responsive genes will provide useful hints for further research on alcohol-induced toxicity and potential therapy.