Endocrine Abstracts

Background and Aims: The transcription factor Gli-similar 3 (GLIS3) plays a key role in the development and maintenance of pancreatic beta-cells as well as in the regulation of Insulin gene expression in adults. Accordingly, genome-wide association studies identified GLIS3 as a susceptibility locus for type 1 diabetes mellitus (T1DM) and glucose metabolism traits. Therefore, the aim of this study was to investigate the association of the rs7020673 (G/C) and rs10758593 (G/A) single nucleotide polymorphisms (SNPs) in the GLIS3 gene with T1DM in a Brazilian population.

Methods: Frequencies of the rs7020673 and rs10758593 SNPs were analyzed in 503 T1DM patients (cases) and in 442 non-diabetic subjects (controls). Genotyping was performed using Real-Time PCR and TaqMan MGB probes (Thermo Scientific). Haplotypes constructed from the combination of these SNPs were inferred using a Bayesian statistical method.

Results: GLIS3 rs7020673C allele frequency was 47.3% in T1DM patients and 45.1% in the non-diabetic group (P=0.365), while the rs10758593A allele was present in 43.3% of cases and 41.1% of controls (P=0.341). Genotype distributions of these SNPs were in agreement with those predicted by Hardy-Weinberg Equilibrium in controls (all P≥0.05), and did not differ significantly between groups (P=0.468 and P=0.279, respectively). In addition, frequencies of rs7020673 and rs10758593 SNPs did not differ between groups under dominant, recessive or additive inheritance models (all P≥0.05). However, frequency of three or more minor alleles of the analyzed SNPs in haplotypes was higher in T1DM patients compared to non-diabetic subjects (6.2 vs 1.6%; P=0.001). Presence of ≥3 minor alleles remained independently associated with risk for T1DM after adjustment for T1DM high-risk HLA DR/DQ haplotypes, age and ethnicity (OR=3.68 95% CI 1.22 – 11.12). Moreover, levels of glycated hemoglobin were higher in T1DM patients carrying the rs10758593A allele than patients with the G/G genotype (8.9±2.1 vs 8.2±2.0; P=0.038). In conclusion, our results indicate that the rs7020673 and rs10758593 SNPs interact in the predisposition for T1DM.