Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Department of Engineering Problems of Ecology, Novosibirsk State Technical University, 630087 Novosibirsk, Russia.
Int J Mol Sci. 2024 Aug 27;25(17):9297. doi: 10.3390/ijms25179297.
The goal of our study was to identify and assess the functionally significant SNPs with potentially important roles in the development of type 2 diabetes mellitus (T2DM) and/or their effect on individual response to antihyperglycemic medication with metformin. We applied a bioinformatics approach to identify the regulatory SNPs (rSNPs) associated with allele-asymmetric binding and expression events in our paired ChIP-seq and RNA-seq data for peripheral blood mononuclear cells (PBMCs) of nine healthy individuals. The rSNP outcomes were analyzed using public data from the GWAS (Genome-Wide Association Studies) and Genotype-Tissue Expression (GTEx). The differentially expressed genes (DEGs) between healthy and T2DM individuals (GSE221521), including metformin responders and non-responders (GSE153315), were searched for in GEO RNA-seq data. The DEGs harboring rSNPs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We identified 14,796 rSNPs in the promoters of 5132 genes of human PBMCs. We found 4280 rSNPs to associate with both phenotypic traits (GWAS) and expression quantitative trait loci (eQTLs) from GTEx. Between T2DM patients and controls, 3810 rSNPs were detected in the promoters of 1284 DEGs. Based on the protein-protein interaction (PPI) network, we identified 31 upregulated hub genes, including the genes involved in inflammation, obesity, and insulin resistance. The top-ranked 10 enriched KEGG pathways for these hubs included insulin, AMPK, and FoxO signaling pathways. Between metformin responders and non-responders, 367 rSNPs were found in the promoters of 131 DEGs. Genes encoding transcription factors and transcription regulators were the most widely represented group and many were shown to be involved in the T2DM pathogenesis. We have formed a list of human rSNPs that add functional interpretation to the T2DM-association signals identified in GWAS. The results suggest candidate causal regulatory variants for T2DM, with strong enrichment in the pathways related to glucose metabolism, inflammation, and the effects of metformin.
我们的研究目标是鉴定和评估具有潜在重要作用的功能显著单核苷酸多态性（SNP），这些 SNP 可能与 2 型糖尿病（T2DM）的发生有关，或对二甲双胍等抗高血糖药物的个体反应有影响。我们应用生物信息学方法，鉴定了与 9 名健康个体外周血单核细胞（PBMC）的 ChIP-seq 和 RNA-seq 配对数据中等位基因不对称结合和表达事件相关的调节性 SNP（rSNP）。使用来自全基因组关联研究（GWAS）和基因型组织表达（GTEx）的公共数据分析 rSNP 结果。在 GEO RNA-seq 数据中搜索了健康个体和 T2DM 个体（GSE221521）之间差异表达的基因（DEG），包括二甲双胍应答者和非应答者（GSE153315）。分析了携带 rSNP 的 DEG，使用基因本体论（GO）和京都基因与基因组百科全书（KEGG）。我们在人类 PBMC 基因的启动子中鉴定了 14796 个 rSNP。我们发现 4280 个 rSNP 与 GTEx 的表型特征（GWAS）和表达数量性状基因座（eQTLs）相关。在 T2DM 患者和对照组之间，在 1284 个 DEG 的启动子中检测到 3810 个 rSNP。基于蛋白质-蛋白质相互作用（PPI）网络，我们确定了 31 个上调的枢纽基因，包括参与炎症、肥胖和胰岛素抵抗的基因。这些枢纽的前 10 个富集 KEGG 途径包括胰岛素、AMPK 和 FoxO 信号通路。在二甲双胍应答者和非应答者之间，在 131 个 DEG 的启动子中发现了 367 个 rSNP。编码转录因子和转录调节因子的基因是最广泛的代表群体，许多基因被证明与 T2DM 的发病机制有关。我们已经形成了一份人类 rSNP 列表，为 GWAS 中鉴定的与 T2DM 相关的信号增加了功能解释。结果表明，候选因果调节变异与 T2DM 有关，在与葡萄糖代谢、炎症和二甲双胍作用相关的途径中富集度很高。
