Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus

BMC Endocrine Disorders

Liangcai Ding¹  Han Yan¹  Lu Chen¹  Mengdi Cai¹  Bo Yan²  Shicheng Lu³  Shuchao Pang⁴ 

[1] Center for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical University, 272100, Jining, Shandong, China;Center for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical University, 272100, Jining, Shandong, China;Shandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Rencheng District, 272029, Jining City, Shandong, China;Division of Endocrinology, Yanzhou People’s Hospital, Jining Medical University, 272100, Jining, Shandong, China;Shandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Rencheng District, 272029, Jining City, Shandong, China;

关键词: Type 2 diabetes mellitus;    Genetics;    GATA4;    Regulatory variants;   

DOI  :  10.1186/s12902-021-00739-0

来源: Springer

【 摘 要 】

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.

【 授权许可】

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