NOTES
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CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
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AUTHOR CONTRIBUTIONS
Conception or design: Y.Y., S.Y., J.M.D., W.C., Y.G.
Acquisition, analysis, or interpretation of data: S.Y., J.M.D.
Drafting the work or revising: S.Y., Y.G.
Final approval of the manuscript: Y.Y., S.Y., J.M.D., W.C., Y.G.
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FUNDING
This study was supported by the National Natural Science Foundation of China (31871264, 81872490), Innovative Talent Promotion Plan of Shaanxi Province for Young Sci-Tech New Star (2018KJXX-010), Natural Science Foundation of Zhejiang Province (LGF18C060002, LWY20H060001), Major Science and Technology Projects in Xiaoshan District (2018224), Natural Science Basic Research Program Shaanxi Province (2018JQ3058) and the Fundamental Research Fund for Central Universities. This study was also supported by the High Performance Computing Platform of Xi’an Jiaotong University and the China Scholarship Council.
Fig. 1Association of the minor allele “A” of rs7785013 with type 2 diabetes mellitus in subjects carrying different genotypes of rs4947941 in the Gene Environment Association Studies (GENEVA) and Institute of Personalized Medicine (IPM) datasets. The odds ratios (ORs) of the association analyses results are shown in the y-axis. TT, subjects carrying “TT” of rs4947941; TC, subjects carrying “TC” of rs4947941; CC, subjects carrying “CC” of rs4947941.
Fig. 2Epigenetic annotation for the region surrounding rs4947941 and rs7785013. The topologically associating domain (TAD) data in the GM12878 cell line were downloaded from the Gene Expression Omnibus (GEO) data, GSE63525. TAD-like domains were identified using promoter capture Hi-C in human pancreatic islets. Chromatin interaction data in multiple cell lines were downloaded from the 4DGenome Database. Active histone modifications, including H3k4me1, H3k4me3, and H3k27ac, in pancreatic islets were obtained from the Roadmap Project using the WashU EpiGenome Browser. EGFR, epidermal growth factor receptor.
Fig. 3Association of the minor allele “A” of rs7785013 with the expression of the epidermal growth factor receptor (EGFR) in the pancreas of subjects carrying different genotypes of rs4947941 in the GTEx Pilot Project. The beta values of the association analyses results are shown in the y-axis. CC, subjects carrying “CC” of rs4947941; TC, subjects carrying “TC” of rs4947941; TT, subjects carrying “TT” of rs4947941.
Fig. 4The results of the differential expression analyses of the epidermal growth factor receptor (EGFR) in diabetic and nondiabetic subjects in the (A) GSE76894, (B) GSE25724, (C) GSE12643, and (D) GSE9006 datasets.
Table 1.Basic characteristics of subjects
Characteristic |
Discovery GENEVA
|
Replication IPM
|
Case |
Control |
Total |
Case |
Control |
Total |
Sample size |
2,558 |
2,983 |
5,541 |
138 |
565 |
703 |
Male/Female |
1,109/1,449 |
1,275/1,708 |
2,384/3,157 |
101/37 |
370/195 |
471/232 |
Age, yr |
57.36±7.71 |
57.12±7.66 |
57.23±7.69 |
58.71±15.32 |
64.83±10.31 |
59.91±14.67 |
Table 2.The interaction SNP pairs identified for type 2 diabetes mellitus
SNP pair |
Chr |
Positiona
|
Geneb
|
Allelec
|
GENEVA
|
IPM
|
Combined P valued
|
MAF |
CR |
OR (95% CI) |
P value |
MAF |
CR |
OR (95% CI) |
P value |
rs4947941 |
7 |
54871175 |
RP11-745C15.2 |
T/C |
0.443 |
1 |
1.00 (0.98–1.02) |
0.824 |
0.424 |
1 |
0.97 (0.92–1.02) |
0.831 |
0.911 |
rs7785013 |
7 |
55152667 |
EGFR |
A/G |
0.158 |
0.999 |
1.00 (0.98–1.03) |
0.830 |
0.137 |
0.999 |
0.98 (0.91–1.05) |
0.977 |
0.998 |
rs494794×rs7785013 |
- |
- |
- |
- |
- |
- |
0.91 (0.88–0.95) |
9.41×10−7
|
- |
- |
0.78 (0.70–0.86) |
1.73×10−6
|
4.84×10−10
|