Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
Department of Pediatrics, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
Immunol Cell Biol. 2021 May;99(5):496-508. doi: 10.1111/imcb.12438. Epub 2021 Feb 24.
The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as to β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision medicine-based therapeutics to prevent or suspend the development of T1D.
1 型糖尿病 (T1D) 发病风险的遗传易感性的概念基础可以追溯到现代人类分子遗传学之前。超过一半的遗传风险归因于人类白细胞抗原 (HLA) Ⅱ类基因区域和胰岛素 (INS) 基因座 - 两者都被认为赋予了自身反应性和组织特异性。尽管如此,对于散布在基因组中的大量微小多基因风险变异体的功能贡献仍存在疑问,这些变异体可能影响疾病异质性和临床结果。在此,我们总结了与本综述时定义的 T1D 相关的编码变异体相关的现有文献,这些基因包括 PTPN22、IFIH1、SH2B3、CD226、TYK2、FUT2、SIRPG、CTLA4、CTSH 和 UBASH3A。总结了来自基因分型人类队列的数据,并介绍了非肥胖型糖尿病 (NOD) 小鼠的研究,以描述这些变异体在先天和适应性免疫以及β细胞脆弱性方面的功能影响,并强调了组织和外周血中的表达谱。讨论了每个变异体对 T1D 分期进展的贡献,包括环境相互作用,并考虑了它们各自的蛋白产物如何作为基于精准医学的治疗方法的有吸引力的靶点,以预防或中止 T1D 的发展。