Graduate Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
Section for Immunobiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
Genes Immun. 2020 Jan;21(1):71-77. doi: 10.1038/s41435-019-0083-y. Epub 2019 Aug 22.
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.
全基因组关联研究已经在 1 型糖尿病（T1D）中涉及 50 多个基因组区域。16p13.13 染色体上的 T1D 区域包括候选基因 CLEC16A 和 DEXI。对于该区域疾病关联的哪个基因是因果关系，目前还没有确凿的证据。我们之前曾报道过，Clecl6a 缺乏会改变免疫反应，并在 1 型糖尿病的非肥胖型糖尿病（NOD）小鼠模型中保护自身免疫。然而，16p13.13 上与糖尿病相关的 SNPs 也被描述为影响 DEXI 的表达，其他人则认为 DEXI 是该疾病位点的因果基因。为了帮助确定 DEXI 是否会影响疾病，我们生成了 Dexi 敲除（KO）NOD 小鼠。我们发现 Dexi 缺乏对糖尿病的发生率没有影响。为了测试 Dexi 和 Clec16a 之间可能存在的相互作用，我们将 Dexi KO 和 Clec16a 敲低（KD）NOD 小鼠进行了杂交。Dexi KO 并没有改变 Clec16a KD 提供的疾病保护作用。我们得出结论，Dexi 在 NOD 模型中的自身免疫性糖尿病中不起作用。我们的数据提供了强烈的暗示性证据，表明 CLEC16A，而不是 DEXI，是 16p13.13 区域变体与 T1D 关联的因果基因。
