PMID- 32602275
OWN - NLM
STAT- MEDLINE
DCOM- 20211015
LR  - 20240219
IS  - 2233-6087 (Electronic)
IS  - 2233-6079 (Print)
IS  - 2233-6079 (Linking)
VI  - 45
IP  - 2
DP  - 2021 Mar
TI  - Enhancer-Gene Interaction Analyses Identified the Epidermal Growth Factor 
      Receptor as a Susceptibility Gene for Type 2 Diabetes Mellitus.
PG  - 241-250
LID - 10.4093/dmj.2019.0204 [doi]
AB  - BACKGROUND: 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. 
      METHODS: 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. RESULTS: We identified one SNP pair, rs4947941xrs7785013, significantly 
      associated with T2DM (combined P=4.84x10-10). 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 rs4947941xrs7785013 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. 
      CONCLUSION: Genetic interaction analyses of enhancers and protein-coding genes 
      suggested that EGFR may be a novel susceptibility gene for T2DM.
FAU - Yang, Yang
AU  - Yang Y
AD  - Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, 
      Xi'an, China.
AD  - Xi'an Center for Disease Control and Prevention, Xi'an, China.
FAU - Yao, Shi
AU  - Yao S
AD  - 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.
FAU - Ding, Jing-Miao
AU  - Ding JM
AD  - 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.
FAU - Chen, Wei
AU  - Chen W
AD  - Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, 
      Xi'an, China.
FAU - Guo, Yan
AU  - Guo Y
AD  - 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.
LA  - eng
GR  - Fundamental Research Funds for the Central Universities/
GR  - XJTU/
GR  - CSC/
GR  - 31871264/National Natural Science Foundation of China/
GR  - 81872490/National Natural Science Foundation of China/
GR  - 2018KJXX-010/Innovative Talent Promotion Plan of Shaanxi Province for Young 
      Sci-Tech New Star/
GR  - LGF18C060002/Natural Science Foundation of Zhejiang Province/
GR  - LWY20H060001/Natural Science Foundation of Zhejiang Province/
GR  - 2018224/Major Science and Technology Projects in Xiaoshan District/
GR  - 2018JQ3058/Natural Science Basic Research Program Shaanxi Province/
GR  - Fundamental Research Fund for Central Universities/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200610
PL  - Korea (South)
TA  - Diabetes Metab J
JT  - Diabetes & metabolism journal
JID - 101556588
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/genetics
MH  - Epistasis, Genetic
MH  - ErbB Receptors
MH  - Humans
MH  - Mice
MH  - Polymorphism, Single Nucleotide/genetics
PMC - PMC8024152
OTO - NOTNLM
OT  - Diabetes mellitus, type 2
OT  - Epistasis, genetic
OT  - ErbB receptors
OT  - Gene regulatory networks
COIS- CONFLICTS OF INTEREST No potential conflict of interest relevant to this article 
      was reported.
EDAT- 2020/07/01 06:00
MHDA- 2021/10/16 06:00
PMCR- 2021/03/01
CRDT- 2020/07/01 06:00
PHST- 2019/11/01 00:00 [received]
PHST- 2020/01/03 00:00 [accepted]
PHST- 2020/07/01 06:00 [pubmed]
PHST- 2021/10/16 06:00 [medline]
PHST- 2020/07/01 06:00 [entrez]
PHST- 2021/03/01 00:00 [pmc-release]
AID - 44.e30 [pii]
AID - dmj-2019-0204 [pii]
AID - 10.4093/dmj.2019.0204 [doi]
PST - ppublish
SO  - Diabetes Metab J. 2021 Mar;45(2):241-250. doi: 10.4093/dmj.2019.0204. Epub 2020 
      Jun 10.