MAY 12, 2016 7:30 AM PDT

Polymorphic miRNA binding sites in the WFS1 gene are risk factors of diabetes mellitus

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Abstract

     Wolframin is a major protein of the endoplasmic reticulum, it is expressed in most tissues and clinical data demonstrate its significant connection to diabetes mellitus. Loss of function mutations of the WFS1 gene result in the monogenic Wolfram-syndrome, characterized by optic atrophy, diabetes insipidus, early onset diabetes mellitus and deafness. Accordingly, polymorphic variants of the gene, which cause only minor alterations in protein function, are putative risk factors of diabetes. This presentation focuses on the association and molecular analysis of two SNPs (rs1046322 and rs9457) in the 3’ UTR region of the WFS1 gene, which are supposed to alter the binding of miRNA-668 and miRNA-185, respectively, based on in-silico data.

     Association analysis of the polymorphic loci and diabetes mellitus was carried out on 617 patients and 1147 health controls in the study. Genotype analysis was carried out using PCR and single base extension (SBE) reaction using the GenomeLab GeXP™ Genetic Analyzer. Functional analysis of miRNA binding was investigated by luciferase reporter system.  The results suggested that rs9457 SNP “C” allele was significantly more frequent among patients with type 2 diabetes mellitus (p = 0.0008), whereas the rs1046322 variant showed a significant association with the type 1 form of the disease. Haplotype analysis confirmed the roles of the polymorphic variants in the genetic background of diabetes. In addition, the luciferase reporter experiments confirmed the data of the sequence analysis in where the rs1046322 and the rs9457 SNPs altered the binding of miRNA-668 and miRNA-185, respectively. Earlier studies indicated an association between a third variant of the 3’ UTR (rs1046320) and diabetes; however no biological function of the SNP could be observed. This is probably due to the strong linkage disequilibrium between rs9457 and rs1046322, thus the latter polymorphism could be a potential genetic marker of rs9457 miRNA-SNP.


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MAY 12, 2016 7:30 AM PDT

Polymorphic miRNA binding sites in the WFS1 gene are risk factors of diabetes mellitus



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