Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
Xi'an Center for Disease Control and Prevention, Xi'an, China.
Diabetes Metab J. 2021 Mar;45(2):241-250. doi: 10.4093/dmj.2019.0204. Epub 2020 Jun 10.
Genetic interactions are known to play an important role in the missing heritability problem for type 2 diabetes mellitus (T2DM). Interactions between enhancers and their target genes play important roles in gene regulation and disease pathogenesis. In the present study, we aimed to identify genetic interactions between enhancers and their target genes associated with T2DM.
We performed genetic interaction analyses of enhancers and protein-coding genes for T2DM in 2,696 T2DM patients and 3,548 controls of European ancestry. A linear regression model was used to identify single nucleotide polymorphism (SNP) pairs that could affect the expression of the protein-coding genes. Differential expression analyses were used to identify differentially expressed susceptibility genes in diabetic and nondiabetic subjects.
We identified one SNP pair, rs4947941×rs7785013, significantly associated with T2DM (combined P=4.84×10-10). The SNP rs4947941 was annotated as an enhancer, and rs7785013 was located in the epidermal growth factor receptor (EGFR) gene. This SNP pair was significantly associated with EGFR expression in the pancreas (P=0.033), and the minor allele "A" of rs7785013 decreased EGFR gene expression and the risk of T2DM with an increase in the dosage of "T" of rs4947941. EGFR expression was significantly upregulated in T2DM patients, which was consistent with the effect of rs4947941×rs7785013 on T2DM and EGFR expression. A functional validation study using the Mouse Genome Informatics (MGI) database showed that EGFR was associated with diabetes-relevant phenotypes.
Genetic interaction analyses of enhancers and protein-coding genes suggested that EGFR may be a novel susceptibility gene for T2DM.
遗传相互作用已知在 2 型糖尿病（T2DM）的遗传缺失问题中发挥重要作用。增强子与其靶基因之间的相互作用在基因调控和疾病发病机制中发挥重要作用。在本研究中，我们旨在鉴定与 T2DM 相关的增强子与其靶基因之间的遗传相互作用。
我们对欧洲血统的 2696 名 T2DM 患者和 3548 名对照进行了 T2DM 增强子和蛋白质编码基因的遗传相互作用分析。线性回归模型用于鉴定可能影响蛋白质编码基因表达的单核苷酸多态性（SNP）对。差异表达分析用于鉴定糖尿病和非糖尿病受试者中差异表达的易感基因。
我们确定了一个 SNP 对 rs4947941×rs7785013，与 T2DM 显著相关（合并 P=4.84×10-10）。SNP rs4947941 被注释为增强子，rs7785013 位于表皮生长因子受体（EGFR）基因中。该 SNP 对与胰腺中 EGFR 表达显著相关（P=0.033），并且 rs7785013 的次要等位基因“T”的增加降低了 EGFR 基因表达，并增加了 rs4947941 的剂量，从而增加了 T2DM 的风险。T2DM 患者中 EGFR 表达显著上调，这与 rs4947941×rs7785013 对 T2DM 和 EGFR 表达的影响一致。使用小鼠基因组信息学（MGI）数据库进行的功能验证研究表明，EGFR 与糖尿病相关表型相关。
增强子和蛋白质编码基因的遗传相互作用分析表明，EGFR 可能是 T2DM 的一个新的易感基因。
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