Table_1_Gene-environment interaction in the pathophysiology of type 1 diabetes.pdf

Type 1 diabetes (T1D) is a complex metabolic autoimmune disorder that affects millions of individuals worldwide and often leads to significant comorbidities. However, the precise trigger of autoimmunity and disease onset remain incompletely elucidated. This integrative perspective article synthesizes the cumulative role of gene-environment interaction in the pathophysiology of T1D. Genetics plays a significant role in T1D susceptibility, particularly at the major histocompatibility complex (MHC) locus and cathepsin H (CTSH) locus. In addition to genetics, environmental factors such as viral infections, pesticide exposure, and changes in the gut microbiome have been associated with the development of T1D. Alterations in the gut microbiome impact mucosal integrity and immune tolerance, increasing gut permeability through molecular mimicry and modulation of the gut immune system, thereby increasing the risk of T1D potentially through the induction of autoimmunity. HLA class II haplotypes with known effects on T1D incidence may directly correlate to changes in the gut microbiome, but precisely how the genes influence changes in the gut microbiome, and how these changes provoke T1D, requires further investigations. These gene-environment interactions are hypothesized to increase susceptibility to T1D through epigenetic changes such as DNA methylation and histone modification, which in turn modify gene expression. There is a need to determine the efficacy of new interventions that target these epigenetic modifications such as “epidrugs”, which will provide novel avenues for the effective management of T1D leading to improved quality of life of affected individuals and their families/caregivers.

1型糖尿病（Type 1 diabetes, T1D）是一种复杂的代谢性自身免疫性疾病，全球数百万人群受其累及，常伴随诸多严重合并症。目前，自身免疫反应的确切触发因素及疾病发作机制仍未完全阐明。本文作为一篇综合评述文章，系统整合了基因-环境交互作用在1型糖尿病病理生理过程中的累积研究证据。遗传因素在1型糖尿病易感性中发挥重要作用，尤其与主要组织相容性复合体（major histocompatibility complex, MHC）位点及组织蛋白酶H（cathepsin H, CTSH）位点密切相关。除遗传因素外，病毒感染、农药暴露及肠道菌群改变等环境因素，也被证实与1型糖尿病的发生存在显著关联。肠道菌群改变可破坏黏膜完整性与免疫耐受，通过分子模拟及肠道免疫系统调控提升肠道通透性，进而可能通过诱导自身免疫反应，增加1型糖尿病的发病风险。已知可影响1型糖尿病发病率的人类白细胞抗原II类（human leukocyte antigen class II, HLA class II）单倍型，或许与肠道菌群改变直接相关，但基因如何调控肠道菌群改变，以及此类改变如何诱发1型糖尿病，仍有待进一步研究探明。现有假说认为，这类基因-环境交互作用可通过DNA甲基化、组蛋白修饰等表观遗传改变，提升1型糖尿病的易感性，进而调控基因表达。当前亟需明确以这类表观遗传修饰为靶点的新型干预手段（如"表观药物（epidrugs）"）的临床疗效，这将为1型糖尿病的有效管理提供全新思路，进而改善患者及其家属/照料者的生活质量。