A complex crosstalk between polymorphic microRNA target sites and AD prognosis

Abstract

Genetic variation associated with different diseases interferes with microRNA-mediated regulation by creating, destroying or modifying microRNA (miRNA) binding sites. Alzheimer disease (AD) is a common neurodegenerative disorder that affects cognitive function in the elderly and has associated genetic variation within the diseased genome. We investigated the extent to which these SNPs interfere with miRNA gene regulation and affect AD susceptibility. We designed a sophisticated computational pipeline to predict the potential miRNA-target SNP interactions followed by a rigorous bioinformatic analysis to establish the effect of "gain-of-function" or "loss-of-function" of the miRNA mediated regulatory network on the etiology of the disease. The significant interactions include target SNPs present in seven genes-related to AD prognosis with the miRNAs-miR-214, -23a & -23b, -486-3p, -30e*, -143, -128, -27a & -27b, -324-5p and -422a. Further our study provides novel insight on the contribution of synonymous mutations towards AD pathogenesis. The putative miRNA::target SNP interactions suggest that the dysregulated miRNA network contributes to the aberrant gene expression in AD. Our results show that miRNA-target variability is a ubiquitous phenomenon in the adult human brain, which may influence gene expression in physiological and pathological conditions. The experimental assay of these miRNA::target SNP predictions will be the next step towards determining the functional effects of these SNPs on miRNA targets and their association with disease susceptibility. Overall, this work may serve as the cornerstones for understanding the variables of the molecular pathways relevant to the development of the disease and designing therapeutic miRNA regimens to modify diseased gene expression profiles in AD patients. © 2011 Landes Bioscience.