Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, China.
Department of Laboratory Medicine, The Second Hospital of Jilin University, Changchun, China.
Front Endocrinol (Lausanne). 2023 Jan 17;13:1050200. doi: 10.3389/fendo.2022.1050200. eCollection 2022.
Diabetes mellitus is a systemic metabolic disorder which may target the lungs and lead to interstitial lung disease. The clinical characteristics and mechanisms of type 2 diabetes mellitus (T2DM) complicated with interstitial lung disease (ILD) have been studied. However, little work has been done to assess genetic contributions to the development of T2DM complicated with ILD.
A pedigree of T2DM complicated with ILD was investigated, and the whole genome re-sequencing was performed to identify the genetic variations in the pedigree. According to the literature, the most valuable genetic contributors to the pathogenesis of T2DM complicated with ILD were screened out, and the related cellular functional experiments were also performed.
A large number of SNPs, InDels, SVs and CNVs were identified in eight subjects including two diabetic patients with ILD, two diabetic patients without ILD, and four healthy subjects from the pedigree. After data analysis according to the literature, SNP rs2943512 (A > C) was considered to be an important potentially pathogenic gene mutation associated with the pathogenesis of ILD in T2DM patients. experiments showed that the expression of MUC5B in BEAS-2B cells was significantly up-regulated by high glucose stimulation, accompanied by the activation of ERK1/2 and the increase of IL-1β and IL-6. When silencing by RNA interference, the levels of p-ERK1/2 as well as IL-1β and IL-6 in BEAS-2B cells were all significantly decreased.
The identification of these genetic variants in the pedigree enriches our understanding of the potential genetic contributions to T2DM complicated with ILD. SNP rs2943512 (A > C) or the up-regulated MUC5B in bronchial epithelial cells may be an important factor in promoting ILD inT2DM patients, laying a foundation for future exploration about the pathogenesis of T2DM complicated with ILD.
糖尿病是一种全身性代谢紊乱疾病，可能会累及肺部，导致间质性肺病。目前已经研究了 2 型糖尿病（T2DM）合并间质性肺疾病（ILD）的临床特征和发病机制。然而，对于评估遗传因素在 T2DM 合并 ILD 中的作用，相关研究还很少。
对一个 T2DM 合并 ILD 的家系进行了研究，并对家系成员进行了全基因组重测序，以鉴定家系中的遗传变异。根据文献筛选出对 T2DM 合并 ILD 发病机制最有价值的遗传贡献者，并进行相关的细胞功能实验。
在该家系的 8 名成员（包括 2 名合并 ILD 的糖尿病患者、2 名不合并 ILD 的糖尿病患者和 4 名健康对照者）中，鉴定出大量的 SNP、InDels、SVs 和 CNVs。根据文献进行数据分析后，发现 SNP rs2943512（A>C）可能是与 T2DM 患者 ILD 发病机制相关的重要潜在致病性基因突变。实验表明，高糖刺激可显著上调 BEAS-2B 细胞中 MUC5B 的表达，同时激活 ERK1/2，并增加 IL-1β和 IL-6 的释放。当通过 RNA 干扰进行沉默时，BEAS-2B 细胞中 p-ERK1/2 以及 IL-1β和 IL-6 的水平均显著降低。
在家系中鉴定出这些遗传变异，丰富了我们对 T2DM 合并 ILD 潜在遗传贡献的认识。SNP rs2943512（A>C）或支气管上皮细胞中 MUC5B 的上调可能是促进 T2DM 患者发生 ILD 的重要因素，为进一步探讨 T2DM 合并 ILD 的发病机制奠定了基础。
