Abstract
Genome-wide association and fine-mapping studies have identified over 40 susceptibility regions for type 1 diabetes (T1D), a common autoimmune disease; however, most of the disease-associated variants are noncoding, and it remains a challenge to understand their biological contributions to T1D pathogenesis. One identified T1D risk locus is located at chromosome 21q22.3 where the most likely candidate gene is UBASH3A, a negative regulator of NF-κB signaling. Various noncoding variants in UBASH3A have been shown to be associated with T1D or other autoimmune diseases. Here we investigated four such SNPs—rs11203202, rs80054410, rs11203203, and rs1893592. We discovered a novel role for rs1893592 in T1D and showed that its minor allele protects against T1D. Our haplotype analysis identified three T1D-associated UBASH3A haplotypes, and revealed that risk for T1D is affected by additive effects of these four UBASH3A variants. In human primary CD4+ T cells, upon T-cell receptor stimulation, the minor allele of rs1893592 was associated with both a significant reduction in the overall mRNA levels of UBASH3A, and an increase in the proportion of a normally occurring, but low-abundant, UBASH3A transcript that retains intron-9 sequences and cannot produce full-length UBASH3A protein. This reduction in UBASH3A, as a consequence of the minor allele at rs1893592, resulted in increased secretion of IL-2, a key cytokine that is required for T-cell activation and function but is deficient in some T1D subjects. Our study provides new mechanistic insights into how rs1893592 affects T1D and autoimmunity, and how interactions between multiple T1D-associated, noncoding variants influence the disease risk.
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Acknowledgements
This research utilizes resources from the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF). This study was supported by NIH grants DK106718 and DK085678 (to PC), and by the JDRF Advanced Postdoctoral Fellowship award 3-APF-2016-177-A-N (to YG).
Funding:
NIH grants DK106718 and DK085678 (to PC), and the JDRF Advanced Postdoctoral Fellowship award 3-APF-2016-177-A-N (to YG).
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Ge, Y., Concannon, P. Molecular-genetic characterization of common, noncoding UBASH3A variants associated with type 1 diabetes. Eur J Hum Genet 26, 1060–1064 (2018). https://doi.org/10.1038/s41431-018-0123-5
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DOI: https://doi.org/10.1038/s41431-018-0123-5
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