Background

Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes.

Scope of review

Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease.

Major conclusions

In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.

中文翻译：

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糖尿病炎症的调节：从遗传学到表观基因组学证据。

背景

糖尿病是全球最大的公共卫生挑战之一，我们仍然缺乏补充方法来显着提高预防和治疗方法的功效。遗传和环境因素是导致糖尿病风险的罪魁祸首。过去十年的证据强调，免疫和炎症反应的失调会增加对 1 型和 2 型糖尿病的易感性。参与免疫细胞极化的基因表达的时空模式取决于响应炎症和代谢线索的基因组增强子元件。几项研究报告称，大多数调控遗传变异位于基因组的非蛋白质编码区，尤其是增强子区。高通量技术的进步已允许对增强子染色质特性进行表征。这些进展支持增强子的基因改变可能影响与糖尿病相关的免疫和炎症反应的概念。

审查范围

全基因组关联研究 (GWAS) 结合功能和综合分析的结果阐明了一些参与免疫系统调节的糖尿病风险相关变异的影响。此外，增强子区域的遗传变异定位可能会改变增强子的状态，这反过来又会导致与糖尿病易感性相关的炎症基因的异常表达。本综述的重点是概述炎症过程在糖尿病的遗传和表观基因组水平上受到调节的当前迹象，以及对可能提高对该疾病理解的未来研究途径的看法。

主要结论

在这篇综述中，我们提供了遗传证据，支持失调的免疫反应是糖尿病的危险因素。我们还讨论了增强子区域在调节免疫细胞极化中的重要性，以及使用全基因组方法识别增强子的最新进展如何能够确定增强子遗传变异对糖尿病发病和表型的影响。这最终可能会导致更好的管理计划和改善人类糖尿病的治疗反应。