Vasoactive Intestinal Peptide Receptor 1 in immune response and autoimmunity: genetic and functional aspects

The human Vasoactive Intestinal Peptide (VIP) is a potent immunosuppressive agent, affecting both innate and adaptive immunity. VPAC1, one of its receptors, has been found to be down-modulated in cells of the immune system in response to activating stimuli. We have studied the role of VPAC1 SNPs in the genetic predisposition to Ankylosing Spondylitis (AS), Idiophatic Achalasia (IA) and Type 2 diabetes (TD2), three multifactorial diseases for which the inflammatory component contribute to their pathogenesis. The Ankylosing Spondylitis association studied performed showed that independently from diseases HLA-B*2705, the AS-associated allele, co-occurs more frequently with allele T at SNP rs896 in the 3’-UTR of VPAC1 gene (p=0.001). For Idiophatic Achalasia we have found an association between SNPs rs437876 and rs896 and the patients with late onset (p=0.0005). We have, also, reported an association between type 2 diabetes and rs9677 in females (ptrend=6x10-4) which correlates with worse clinical parameters. These genetic studies have indicated an association especially with SNPs mapping in the 3'-UTR of VPAC1, prompting us to perform functional studies in monocytes. We have found an association between the presence of a T at rs896 in VPAC1 3’-UTR, and a sharp reduction of VPAC1 expression, both at mRNA and protein level after LPS treatment. Moreover, we have selected a microRNAs, miR-525-5p, as having its putative target sequence next to SNP rs896. We have found that this miRNA is upregulated during inflammation in monocytes and that it has, among its targets, VPAC1, therefore inducing its down-regulation. Taken together, these studies shed light in some of the aspects of the complex regulatory network controlling VPAC1 expression and inflammation.