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The type 1 diabetes candidate gene Dexi does not affect disease risk in the nonobese diabetic mouse model

Genes & Immunity volume 21, pages 71–77 (2020)Cite this article

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Abstract

Genome-wide association studies have implicated more than 50 genomic regions in type 1 diabetes (T1D). A T1D region at chromosome 16p13.13 includes the candidate genes CLEC16A and DEXI. Conclusive evidence as to which gene is causal for the disease association of this region is missing. We previously reported that Clec16a deficiency modified immune reactivity and protected against autoimmunity in the nonobese diabetic (NOD) mouse model for T1D. However, the diabetes-associated SNPs at 16p13.13 were described to also impact on DEXI expression and others have argued that DEXI is the causal gene in this disease locus. To help resolve whether DEXI affects disease, we generated Dexi knockout (KO) NOD mice. We found that Dexi deficiency had no effect on the frequency of diabetes. To test for possible interactions between Dexi and Clec16a, we intercrossed Dexi KO and Clec16a knockdown (KD) NOD mice. Dexi KO did not modify the disease protection afforded by Clec16a KD. We conclude that Dexi plays no role in autoimmune diabetes in the NOD model. Our data provide strongly suggestive evidence that CLEC16A, not DEXI, is causal for the T1D association of variants in the 16p13.13 region.

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Acknowledgements

We thank John Stockton for embryo microinjections, and also thank Charles Evavold for advice on BM-DM experiments and providing conditioned media. JMNB was supported by a pre-doctoral training fellowship from NIDDK (T32DK007260). This research was funded in part by a grant from NIDDK (R56DK109954-01) to SK and supported by core facilities funded by the NIDDK Diabetes Research Center award P30DK036836 to the Joslin Diabetes Center.

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Authors and Affiliations

  1. Graduate Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA

    Janice M. Nieves-Bonilla

  2. Section for Immunobiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Janice M. Nieves-Bonilla, Badr Kiaf, Cornelia Schuster & Stephan Kissler

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  1. Janice M. Nieves-Bonilla
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  2. Badr Kiaf
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  3. Cornelia Schuster
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  4. Stephan Kissler
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Contributions

JMNB performed experiments, analyzed data, and wrote the manuscript. BK performed experiments. CS helped with experimental design and data interpretation. SK supervised the study, analyzed data, and wrote the manuscript. SK is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Stephan Kissler.

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Nieves-Bonilla, J.M., Kiaf, B., Schuster, C. et al. The type 1 diabetes candidate gene Dexi does not affect disease risk in the nonobese diabetic mouse model. Genes Immun 21, 71–77 (2020). https://doi.org/10.1038/s41435-019-0083-y

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