Exploring the Epigenetic Regulatory Role of m6A-Associated SNPs in Type 2 Diabetes Pathogenesis

Miao Chen; Weimin Lin; Jianru Yi; Zhihe Zhao

doi:10.2147/PGPM.S334346

Exploring the Epigenetic Regulatory Role of m6A-Associated SNPs in Type 2 Diabetes Pathogenesis

Pharmgenomics Pers Med. 2021 Oct 27:14:1369-1378. doi: 10.2147/PGPM.S334346. eCollection 2021.

Authors

Miao Chen^{1

2}, Weimin Lin¹, Jianru Yi^{1

2}, Zhihe Zhao^{1

2}

Affiliations

¹ State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China.
² Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China.

Abstract

Purpose: Genetic factors in type 2 diabetes (T2D) pathogenesis have been widely explored by the genome-wide association studies (GWAS), identifying a great amount of susceptibility loci. With the development of high-resolution sequencing, the N(6)-methyladenosine (m6A) RNA modification has been proved to be affected by genetic variation. In this study, we identified the T2D-associated m6A-SNPs from T2D GWAS data and explored the underlying mechanism of the pathogenesis of T2D.

Methods: We examined the association of m6A-SNPs with T2D among large-scale T2D GWAS summary statistics and further performed multi-omics integrated analysis to explore the potential role of the identified m6A-SNPs in T2D pathogenesis.

Results: Among the 15,124 T2D-associated m6A-SNPs, 71 of them reach the genome-wide significant threshold (5.0e-05). The leading SNP rs4993986 (C>G), which is located near the m6A modification site at the 3' end of the HLA-DQB1 transcript, is expected to participate in the pathogenesis of T2D by influencing m6A modification to regulate the HLA-DQB1 expression.

Conclusion: The current study has suggested a potential correlation between m6A-SNPs and T2D pathogenesis and also provided new insights into the pathogenic mechanism of the T2D susceptibility loci identified by GWAS.

Keywords: epigenetics; genome-wide association study; m6A; single nucleotide polymorphism; type 2 diabetes.

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (grant no. 81801018, 81771048), Research and Development Program, West China Hospital of Stomatology Sichuan Univercity (RD-03-202012), and Sichuan Science and Technology Program (grant no. 2020YFS0170).