Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Nat Rev Endocrinol. 2023 Aug;19(8):477-486. doi: 10.1038/s41574-023-00836-1. Epub 2023 May 11.
Existing therapies for type 2 diabetes mellitus (T2DM) show limited efficacy or have adverse effects. Numerous genetic variants associated with T2DM have been identified, but progress in translating these findings into potential drug targets has been limited. Here, we describe the tools and platforms available to identify effector genes from T2DM-associated coding and non-coding variants and prioritize them for functional studies. We discuss QSER1 and SLC12A8 as examples of genes that have been identified as possible T2DM candidate genes using these tools and platforms. We suggest further approaches, including the use of sequencing data with increased sample size and ethnic diversity, single-cell omics data for analyses, glycaemic trait associations to predict gene function and, potentially, human induced pluripotent stem cell 'village' cultures, to strengthen current gene functionalization workflows. Effective prioritization of T2DM-associated genes for experimental validation could expedite our understanding of the genetic mechanisms responsible for T2DM to facilitate the use of precision medicine in its treatment.
现有的 2 型糖尿病（T2DM）治疗方法疗效有限或有不良反应。已经发现了许多与 T2DM 相关的遗传变异，但将这些发现转化为潜在药物靶点的进展有限。在这里，我们描述了可用于从与 T2DM 相关的编码和非编码变异中识别效应基因并对其进行功能研究的工具和平台。我们讨论了 QSER1 和 SLC12A8 作为使用这些工具和平台确定为可能的 T2DM 候选基因的基因的例子。我们建议进一步采用包括增加样本量和种族多样性的测序数据、单细胞组学数据进行分析、血糖特征关联预测基因功能，以及潜在的人类诱导多能干细胞“村落”培养等方法，以加强当前的基因功能化工作流程。有效的 T2DM 相关基因实验验证优先级排序可以加速我们对导致 T2DM 的遗传机制的理解，从而促进精准医学在其治疗中的应用。
