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Beyond Genetics: What Causes Type 1 Diabetes

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Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell-mediated β cell destruction in the pancreas of genetically susceptible individuals. Extensive familial and population genetic studies uncovered the strong linkage and association between HLA gene variants and T1D. Non-HLA genes have also been associated with T1D, such as INS, CTLA4, and PTPN22. T1D is considered as one of the most heritable common diseases. However, evidence that monozygotic twins have incomplete concordance of disease susceptibility provides convincing proof that environmental factors also play important roles in the pathogenesis of the disease. Environmental factors can induce the alterations of gene expression via epigenetic mechanisms. Epigenetic modifications refer to the alterations in gene expression without changes of the DNA sequence, but instead occur as a result of DNA methylation, histone modifications, and miRNA regulation. Aberrant epigenetic modifications will cause the dysregulation of gene expression, thus leading to a variety of human diseases. There are significant differences in DNA methylation, histone modifications, and miRNA profiling found in T1D patients compared with healthy individuals. Epigenetic modifications contribute to the pathogenesis of T1D mainly by regulating the expression of susceptible genes in T1D. These susceptible genes are involved in antigen presentation (such as HLA), immune tolerance (such as FOXP3 and CTLA4), autoreactive T cell response (such as GAD65), and β cell functions (such as INS). A better understanding of epigenetic mechanisms for regulating susceptible genes of T1D will help identify candidates that target epigenetic pathways to control and/or prevent T1D. Knowledge of epigenetic changes in T1D also provides us with potential biomarkers for diagnosis, prognostication, personalized treatment, and prevention of the disease.

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Acknowledgements

We thank Dr. M. Eric Gershwin for the help with this manuscript. This work was supported by the National Natural Science Foundation of China (Grant Nos. 81300648 and 81170725), Hunan Provincial Natural Science Foundation of China (15JJ3132).

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Authors and Affiliations

  1. Diabetes Center, 2nd Xiangya Hospital, and Institute of Metabolism and Endocrinology, Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, 139 Renmin Middle Rd, Changsha, Hunan, 410011, China

    Zhen Wang, Zhiguo Xie & Zhiguang Zhou

  2. Department of Dermatology, 2nd Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, 139 Renmin Middle Rd, Changsha, Hunan, 410011, China

    Qianjin Lu

  3. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, USA

    Christopher Chang

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  1. Zhen Wang
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  2. Zhiguo Xie
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  3. Qianjin Lu
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  4. Christopher Chang
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  5. Zhiguang Zhou
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Correspondence to Zhiguang Zhou.

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Wang, Z., Xie, Z., Lu, Q. et al. Beyond Genetics: What Causes Type 1 Diabetes. Clinic Rev Allerg Immunol 52, 273–286 (2017). https://doi.org/10.1007/s12016-016-8592-1

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