Abstract
BackgroundType 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Genetics plays a critical role in T2D etiology. Transcription factor GATA4 is required for the pancreatic development, and GATA4 gene mutations are implicated in neonatal or childhood-onset diabetes. In this study, we aimed to investigate whether regulatory variants in GATA4 gene may change GATA4 levels, conferring susceptibility to T2D development.MethodsThe promoter region of GATA4 gene was analyzed by targeted sequencing in T2D patients (n = 255) and ethnic-matched controls (n = 371). Dual luciferase activity assay was used for functional study, and EMSA (electrophoretic mobility shift assay) was performed for detecting transcription factor binding.ResultsThirteen regulatory variants including 5 SNPs were identified. A novel heterozygous variant (32124C > T) and one SNP [31487C > G (rs1053351749)] were only identified in T2D. Both regulatory variants significantly affected GATA4 gene promoter activity in cultured HEK-293 and INS-1 cells. Furthermore, the variant (32124C > T) evidently enhanced the binding of unknown transcriptional activator.ConclusionsOur data suggested that GATA4 gene regulatory variants may contribute to T2D development as a rare risk factor.
Highlights
Type 2 diabetes mellitus (T2D) is a common and complex disease
We aimed to investigate whether regulatory variants in Transcription factor GATA4 (GATA4) gene may change GATA4 levels, conferring susceptibility to T2D development
To determine tissue-specific effects of the regulatory variants, we examined the GATA4 gene promoter activity in Rat insulinoma cells (INS-1) cells (Fig. 2b)
Summary
Type 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Transcription factor GATA4 is required for the pancreatic development, and GATA4 gene mutations are implicated in neonatal or childhood-onset diabetes. Type 2 diabetes mellitus (T2D) is a common and complex disease and caused by interactions between genetic and environmental factors [1]. GATA4 gene is expressed in mesoderm and endoderm derived tissues, including pancreas in mice [5]. Mice with GATA4 gene deletion die before birth, mainly due to severe defects in heart morphogenesis and ventral foregut closure [7, 8]. GATA4 deficiency causes ectopic pancreas, which contains all three pancreatic lineage cells [11].
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