The type 1 diabetes (T1D) risk locus on chromosome 15q25.1 harbors the candidate gene CTSH (cathepsin H). We previously demonstrated that CTSH regulates β-cell function in vitro and in vivo. CTSH overexpression protected insulin-secreting INS-1 cells against cytokine-induced apoptosis. The purpose of the present study was to identify the genes through which CTSH mediates its protective effects. Microarray analysis identified 63 annotated genes differentially expressed between CTSH-overexpressing INS-1 cells and control cells treated with interleukin-1β and interferon-γ for up to 16h. Permutation test identified 10 significant genes across all time-points: Elmod1, Fam49a, Gas7, Gna15, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified the “Inflammation mediated by chemokine and cytokine signaling pathway” with Gna15, Ptgs1 and Rac2 as significant. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis, suggesting that the small GTPase and T1D candidate gene Rac2 contributes to the anti-apoptotic effect of CTSH.

染色体 15q25.1 上的 1 型糖尿病 (T1D) 风险位点包含候选基因 CTSH（组织蛋白酶 H）。我们之前证明 CTSH 在体外和体内调节 β 细胞功能。 CTSH 过表达可保护分泌胰岛素的 INS-1 细胞免受细胞因子诱导的细胞凋亡。本研究的目的是确定 CTSH 通过哪些基因介导其保护作用。微阵列分析鉴定出 63 个注释基因在 CTSH 过表达 INS-1 细胞和用白细胞介素 1β 和干扰素 γ 处理长达 16 小时的对照细胞之间存在差异表达。排列测试确定了所有时间点的 10 个重要基因：Elmod1、Fam49a、Gas7、Gna15、Msrb3、Nox1、Ptgs1、Rac2、Scn7a 和 Ttn。通路分析确定“趋化因子和细胞因子信号通路介导的炎症”，其中 Gna15、Ptgs1 和 Rac2 具有显着性。 Rac2 的敲除消除了 CTSH 过表达对细胞因子诱导的细胞凋亡的保护作用，表明小 GTPase 和 T1D 候选基因 Rac2 有助于 CTSH 的抗凋亡作用。