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Enhancer-Gene Interaction Analyses Identified the Epidermal Growth Factor Receptor as a Susceptibility Gene for Type 2 Diabetes Mellitus.

Authors
  • Yang, Yang1, 2
  • Yao, Shi3
  • Ding, Jing-Miao3
  • Chen, Wei1
  • Guo, Yan3
  • 1 Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. , (China)
  • 2 Xi'an Center for Disease Control and Prevention, Xi'an, China. , (China)
  • 3 Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. , (China)
Type
Published Article
Journal
Diabetes & metabolism journal
Publication Date
Mar 01, 2021
Volume
45
Issue
2
Pages
241–250
Identifiers
DOI: 10.4093/dmj.2019.0204
PMID: 32602275
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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.

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