Single Nucleotide Polymorphisms in the 3′UTR of VPAC-1 Cooperate in Modulating Gene Expression and Impact Differently on the Interaction with miR525-5p

Complex immune and neurodegenerative disorders are the result of multiple interactions between common genetic variations having, individually, a weak effect on the disease susceptibility or resistance. Interestingly, some genes have been found to be associated with more than one disease although not necessarily the same SNPs are involved. In this context, single nucleotide polymorphisms in the 3′UTR region of type 1 receptor (VPAC-1) for vasoactive intestinal peptide (VIP) have been reported to be associated with some immune-mediated as well as with neurodegenerative diseases such as Alzheimer's Disease (AD). Here, we demonstrate that variations at the 3′UTR of the VPAC-1 gene act synergistically to affect the expression of the luciferase as well as of the GFP reporter genes expressed in HEK293T cells. Moreover, the miRNA 525-5p, previously shown by us to target the 3′UTR of VPAC-1, is more efficient in decreasing GFP expression when co-expressed with constructs carrying the allele C at rs896 (p<10(-3)) suggesting that this miRNA regulates VPAC-1 expression at different levels depending on rs896 polymorphism and thus adding complexity to the network of disease susceptibility.