P055 : INS-VNTR POLYMORPHISM AND GENE EXPRESSION IN TYPE 1, TYPE 2 AND GESTATIONAL IN BRAZILIAN DIABETES MELLITUS PATIENTS

Abstract

Besides HLA class II alleles, the variable number of tandem repeat polymorphism located at 5’ of the insulin gene (INS-VNTR) at chromosome 11p15.5 is the second most important susceptibility region to type 1 diabetes (T1D). INS-VNTR alleles (ACAGGGGTGTGGGG) is divided into class I (30–60 repeats), class II (60–120) and class III (120–160). INS-VNTR class I allele transcribe lower thymic INS than class III allele favoring escape of auto-reactive thymocytes from negative selection. Since insulin resistance is a major shared feature among diabetes patients and since there no studies evaluating these markers in the major types of the disease, we characterized the INS-VNTR polymorphisms (348patients/339controls) and the differential mRNA/microRNA (40 patients) expression in T1D, gestational (GDM) and type 2 (T2D) Brazilian diabetic patients. INS-VNTR was performed using −23HphI PCR-RFLP, and gene expression profiles were performed using Agilent microarrays. INS-VNTR I:I genotype was associated with susceptibility, whereas the III:III genotype conferred protection against T1D development, and I:III genotype was associated to T2D. The multivariate analyses results showed that the I:I genotype was associated with age and dyslipidemia only in T1D patients. Considering all types of diabetes, the differential gene expression profiles (mRNA/miRNA) for INS-VNTR I:I genotype were distinct from those observed for the III:III genotype. The miRNA expression profile according to INS-VNTR polymorphism yielded 31 differentially expressed transcripts. Networks of functional miRNA target, presenting possible INS interactions, showed 6 upregulated ( I:I genotype), 10 upregulated (I:III genotype), and 6 upregulated and 8 downregulated for III:III genotype. Conclusion: This is the first study of INS-VNTR polymorphisms evaluating the three major types of diabetes in the same population group. Moreover, the INS-VNTR genotypes influenced gene and miRNAs expression profiles.