Next steps in the identification of gene targets for type 1 diabetes.
Next steps in the identification of gene targets for type 1 diabetes.
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DOI：
10.1007/s00125-020-05248-8
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发表时间：
2020-11
期刊：
影响因子：
8.2
通讯作者：
Rich SS
中科院分区：
文献类型：
--
作者：
Grant SFA;Wells AD;Rich SS
本综述的目的是提供一个未来的基因组学和其他组学方法在定义的遗传贡献的所有阶段的1型糖尿病的风险和功能的影响和相关的变异的临床实施。从近50年前认识到遗传学（以HLA的形式）将1型糖尿病的风险与2型糖尿病区分开来，技术的进步和通过合作获得的样本已经确定了60多个与1型糖尿病风险相关的SNP位点。与HLA区域基因相结合，这些变异占遗传风险的大部分（约占总风险的50%）;然而，相对较少的变异位于产生预测蛋白质变化的基因的编码区。1型糖尿病的绝大多数遗传风险似乎归因于参与基因调控的基因组区域，但这些遗传变异的靶效应子并不容易识别。尽管过去的遗传学研究清楚地表明与风险有关的免疫相关细胞类型，但靶器官（β细胞）并未受到影响。通过新兴技术，使用遗传学，基因表达，表观遗传学，染色体构象和基因编辑的组合，SNP如何调节基因的新景观已经出现。此外，免疫系统和β细胞及其生物学途径都以特定于环境的方式受到影响。使用免疫和β细胞研究的变异将1型糖尿病与2型糖尿病区分开来，当它们结合在遗传风险评分中时，为预测和治疗开辟了新的途径。本文的在线版本（10.1007/s 00125 -020-05248-8）包含一张图的幻灯片，可供授权用户下载。
The purpose of this review is to provide a view of the future of genomics and other omics approaches in defining the genetic contribution to all stages of risk of type 1 diabetes and the functional impact and clinical implementations of the associated variants. From the recognition nearly 50 years ago that genetics (in the form of HLA) distinguishes risk of type 1 diabetes from type 2 diabetes, advances in technology and sample acquisition through collaboration have identified over 60 loci harbouring SNPs associated with type 1 diabetes risk. Coupled with HLA region genes, these variants account for the majority of the genetic risk (~50% of the total risk); however, relatively few variants are located in coding regions of genes exerting a predicted protein change. The vast majority of genetic risk in type 1 diabetes appears to be attributed to regions of the genome involved in gene regulation, but the target effectors of those genetic variants are not readily identifiable. Although past genetic studies clearly implicated immune-relevant cell types involved in risk, the target organ (the beta cell) was left untouched. Through emergent technologies, using combinations of genetics, gene expression, epigenetics, chromosome conformation and gene editing, novel landscapes of how SNPs regulate genes have emerged. Furthermore, both the immune system and the beta cell and their biological pathways have been implicated in a context-specific manner. The use of variants from immune and beta cell studies distinguish type 1 diabetes from type 2 diabetes and, when they are combined in a genetic risk score, open new avenues for prediction and treatment. Graphical abstract The online version of this article (10.1007/s00125-020-05248-8) contains a slide of the figure for download, which is available to authorised users.
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