Genome-Wide Identification of

Objectives: N6-methyladenosine (m6A) is essential in the regulation of the immune system, but the role that its single nucleotide polymorphisms (SNPs) play in the pathogenesis of type 1 diabetes (T1D) remains unknown. This study demonstrated the association between genetic variants in m6A regulators and T1D risk based on a case-control study in a Chinese population. Methods: The tagging SNPs in m6A regulators were genotyped in 1005 autoantibody-positive patients with T1D and 1257 controls using the Illumina Human OmniZhongHua-8 platform. Islet-specific autoantibodies were examined by radioimmunoprecipitation in all the patients. The mixed-meal glucose tolerance test was performed on 355 newly diagnosed patients to evaluate their residual islet function. The functional annotations for the identified SNPs were performed in silico. Using 102 samples from a whole-genome expression microarray, key signaling pathways associated with m6A regulators in T1D were comprehendingly evaluated. Results: Under the additive model, we observed three tag SNPs in the noncoding region of the PRRC2A (rs2260051, rs3130623) and YTHDC2 (rs1862315) gene are associated with T1D risk. Although no association was found between these SNPs and islet function, patients carrying risk variants had a higher positive rate for ZnT8A, GADA, and IA-2A. Further analyses showed that rs2260051[T] was associated with increased expression of PRRC2A mRNA ( Conclusion: This study found intronic variants in PRRC2A and YTHDC2 associated with T1D risk in a Chinese Han population. PRRC2A rs2260051[T] may be implicated in unbalanced immune homeostasis by affecting the expression of PRRC2A mRNA. These findings enriched our understanding of m6A regulators and their intronic SNPs that underlie the pathogenesis of T1D.