Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes
ObjectivesN6-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 a...
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.913345/full |
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| author | Yang Chen Min Shen Chen Ji Yanqian Huang Yun Shi Li Ji Yao Qin Yong Gu Qi Fu Heng Chen Kuanfeng Xu Tao Yang |
| author_facet | Yang Chen Min Shen Chen Ji Yanqian Huang Yun Shi Li Ji Yao Qin Yong Gu Qi Fu Heng Chen Kuanfeng Xu Tao Yang |
| author_sort | Yang Chen |
| collection | DOAJ |
| description | ObjectivesN6-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.MethodsThe 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.ResultsUnder 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 (P = 7.0E-13), and PRRC2A mRNA was significantly higher in peripheral blood mononuclear cell samples from patients with T1D compared to normal samples (P = 0.022). Enrichment analyses indicated that increased PRRC2A expression engages in the most significant hallmarks of cytokine-cytokine receptor interaction, cell adhesion and chemotaxis, and neurotransmitter regulation pathways. The potential role of increased PRRC2A in disrupting immune homeostasis is through the PI3K/AKT pathway and neuro-immune interactions.ConclusionThis 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. |
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| last_indexed | 2024-12-12T13:06:58Z |
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| spelling | doaj.art-d6f969dbd1ae4cd39d618493253951792022-12-22T00:23:37ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-06-011310.3389/fendo.2022.913345913345Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 DiabetesYang Chen0Min Shen1Chen Ji2Yanqian Huang3Yun Shi4Li Ji5Yao Qin6Yong Gu7Qi Fu8Heng Chen9Kuanfeng Xu10Tao Yang11Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, ChinaDepartment of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaObjectivesN6-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.MethodsThe 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.ResultsUnder 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 (P = 7.0E-13), and PRRC2A mRNA was significantly higher in peripheral blood mononuclear cell samples from patients with T1D compared to normal samples (P = 0.022). Enrichment analyses indicated that increased PRRC2A expression engages in the most significant hallmarks of cytokine-cytokine receptor interaction, cell adhesion and chemotaxis, and neurotransmitter regulation pathways. The potential role of increased PRRC2A in disrupting immune homeostasis is through the PI3K/AKT pathway and neuro-immune interactions.ConclusionThis 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.https://www.frontiersin.org/articles/10.3389/fendo.2022.913345/fullm6A (N6-methyladenosine)type 1 diabetes (T1D)single nucleotide polymorphismautoimmune diseaseintronic variant |
| spellingShingle | Yang Chen Min Shen Chen Ji Yanqian Huang Yun Shi Li Ji Yao Qin Yong Gu Qi Fu Heng Chen Kuanfeng Xu Tao Yang Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes Frontiers in Endocrinology m6A (N6-methyladenosine) type 1 diabetes (T1D) single nucleotide polymorphism autoimmune disease intronic variant |
| title | Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes |
| title_full | Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes |
| title_fullStr | Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes |
| title_full_unstemmed | Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes |
| title_short | Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes |
| title_sort | genome wide identification of n6 methyladenosine associated snps as potential functional variants for type 1 diabetes |
| topic | m6A (N6-methyladenosine) type 1 diabetes (T1D) single nucleotide polymorphism autoimmune disease intronic variant |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.913345/full |
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