Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Nat Rev Endocrinol. 2020 Apr;16(4):202-212. doi: 10.1038/s41574-020-0325-0. Epub 2020 Feb 25.
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent multifactorial disease that has both genetic and environmental risk factors, resulting in impaired glucose homeostasis. Genome-wide association studies (GWAS) have identified over 400 genetic signals that are associated with altered risk of T2DM. Human physiology and epigenomic data support a central role for the pancreatic islet in the pathogenesis of T2DM. This Review focuses on the promises and challenges of moving from genetic associations to molecular mechanisms and highlights efforts to identify the causal variant and effector transcripts at T2DM GWAS susceptibility loci. In addition, we examine current human models that are used to study both β-cell development and function, including EndoC-β cell lines and human induced pluripotent stem cell-derived β-like cells. We use examples of four T2DM susceptibility loci (CDKAL1, MTNR1B, SLC30A8 and PAM) to emphasize how a holistic approach involving genetics, physiology, and cellular and developmental biology can disentangle disease mechanisms at T2DM GWAS signals.
2 型糖尿病（T2DM）是一种日益流行的多因素疾病，具有遗传和环境风险因素，导致葡萄糖稳态受损。全基因组关联研究（GWAS）已经确定了 400 多个与 T2DM 风险改变相关的遗传信号。人类生理学和表观基因组学数据支持胰岛在 T2DM 发病机制中的核心作用。本综述重点介绍了从遗传关联到分子机制的进展，并强调了确定 T2DM GWAS 易感位点的因果变异和效应转录本的努力。此外，我们还研究了目前用于研究β细胞发育和功能的人类模型，包括 EndoC-β 细胞系和人诱导多能干细胞衍生的β样细胞。我们使用四个 T2DM 易感性位点（CDKAL1、MTNR1B、SLC30A8 和 PAM）的例子来说明如何通过涉及遗传学、生理学以及细胞和发育生物学的整体方法来阐明 T2DM GWAS 信号中的疾病机制。
