CREB1 functional polymorphisms modulating promoter transcriptional activity are associated with type 2 diabetes...

The cAMP responsive element binding protein 1 (CREB1) is a ubiquitous transcription factor that contributes to the regulation of gluconeogenesis. The mechanisms of the CREB1 function remain largely unknown. In this study, we aimed to explore genetic variations in CREB1 promoter region and determine whether these loci affect transcriptional activity and risk on type 2 diabetes (T2D). Three polymorphisms were identified and designated as MU₁, MU₂ and MU₃, respectively. Genotypic distribution analysis revealed that MU₁ genotypes presented similar distribution between T2D and healthy controls (P > 0.05), while the MU₂ and MU₃ showed significant differences (P < 0.05). Haplotypic blocks of the three loci were constructed, and H1-TGA, H2-TTT and H3-ATT had higher frequencies in T2D patients than those in controls. Association studies revealed that the three loci significantly affected plasma glucose, glycated hemoglobin and insulin secretion. Disequilibrium analysis identified that the MU₂ and MU₃ variants were strongly linked in T2D (r² = 0.348, D' = 1.0). Further analysis indicated that MU₂ (TT vs GG, OR = 2.38, 95%CI = 1.19-4.77, P = 0.01) and MU₃ (AA vs TT, OR = 1.16, 95%CI = 1.19-4.77, P = 0.04) were significantly associated with T2D in dominant genotypes. Luciferase assay showed that T-A haplotype from the highly linked MU₂ and MU₃ exhibited maximal promoter activity, which was consistent with the correlation results. We concluded that the TT genotype of MU₂ and the AA genotype of MU₃ could be used as molecular markers for evaluating the risk on T2D.