美国范德比尔特大学Marcela Brissova等研究人员合作发现，遗传风险汇聚于介导早期2型糖尿病的调控网络。2023年12月4日，《自然》杂志在线发表了这项成果。

研究人员表示，2型糖尿病（T2D）是全球发病率和死亡率的主要原因，其特征是胰岛β细胞分泌胰岛素的功能障碍。T2D全基因组关联研究（GWAS）已在非编码和β细胞调控基因组区域发现了数百个信号，但破译其生物学机制仍具有挑战性。

为了确定早期疾病驱动事件，研究人员对早期T2D和对照供体进行了传统和多重胰腺组织成像、分选胰岛细胞转录组学和胰岛功能分析。通过整合多种模式，研究人员发现早期T2D的特征是β细胞内在缺陷，这些缺陷可被配比为基因调控模块，其中富含遗传风险信号。在确定了其中一个模块中的β细胞枢纽基因和转录因子RFX6后，研究人员展示了多层遗传风险，这些风险汇聚到RFX6介导的网络中，并减少了β细胞的胰岛素分泌。

原代人类胰岛细胞中的RFX6干扰会改变T2D GWAS信号富集区的β细胞染色质结构，人群规模的遗传分析将RFX6表达的减少与T2D风险的增加联系在一起。要了解复杂的全身性疾病的分子机制，就必须整合来自多个分子、细胞、器官和个体的信号，因此研究人员预计这种方法将成为一种有用的模板，可用于利用GWAS数据鉴定和验证其他疾病或性状的关键调控网络和核心枢纽基因。

附：英文原文

Title: Genetic risk converges on regulatory networks mediating early type 2 diabetes

Author: Walker, John T., Saunders, Diane C., Rai, Vivek, Chen, Hung-Hsin, Orchard, Peter, Dai, Chunhua, Pettway, Yasminye D., Hopkirk, Alexander L., Reihsmann, Conrad V., Tao, Yicheng, Fan, Simin, Shrestha, Shristi, Varshney, Arushi, Petty, Lauren E., Wright, Jordan J., Ventresca, Christa, Agarwala, Samir, Aramandla, Radhika, Poffenberger, Greg, Jenkins, Regina, Mei, Shaojun, Hart, Nathaniel J., Phillips, Sharon, Kang, Hakmook, Greiner, Dale L., Shultz, Leonard D., Bottino, Rita, Liu, Jie, Below, Jennifer E., Parker, Stephen C. J., Powers, Alvin C., Brissova, Marcela

Issue&Volume: 2023-12-04

Abstract: Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3,4,5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by β cells. RFX6 perturbation in primary human islet cells alters β cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

DOI: 10.1038/s41586-023-06693-2

Source: https://www.nature.com/articles/s41586-023-06693-2