BackgroundImpaired regulatory T cell immunity plays a central role in the development of type 1 diabetes (T1D). Interleukin-2 receptor (IL-2R) signaling is essential for regulatory T cells (TREG), and cytokine-inducible SH2-containing protein (CIS) regulates IL-2R signaling as a feedback inhibitor. Previous studies identified association of CISH promoter region single nucleotide polymorphisms (SNPs) with susceptibility to infectious diseases.MethodsHere we analyzed allele frequencies of three CISH SNPs (i.e., rs809451, rs414171, rs2239751) in a study of T1D patients (n = 260, onset age < 5 years, duration > 10 years). Minor allele frequencies were compared to a control cohort of the 1000 Genomes Project. Assigned haplotypes were determined for effects on T1D manifestation and severity. Finally, the CISH haplotype influence on cytokine signaling and function was explored in T cells from healthy donors.ResultsWe detected similar minor allele frequencies between T1D patients and the control cohort. T1D onset age, residual serum C-peptide level, and insulin requirement were comparable between different haplotypes. Only minor differences between the haplotypes were found for in vitro cytokine (i.e., IL-2, IL-7)-induced CIS mRNA expression. STAT5 phosphorylation was induced by IL-2 or IL-7, but no differences were found between the haplotypes. TREG purified from healthy donors with the two most common haplotypes showed similar capacity to inhibit heterologous effector T cells.ConclusionsThis study provides no evidence for an association of CISH promoter SNPs with susceptibility to T1D or severity of disease. In contrast to previous studies, no influence of different haplotypes on CIS mRNA expression or T cell-mediated functions was found.

中文翻译：

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CISH启动子多态性对T细胞细胞因子受体信号和1型糖尿病易感性的影响

背景受损的调节性 T 细胞免疫在 1 型糖尿病 (T1D) 的发展中起着核心作用。白细胞介素 2 受体 (IL-2R) 信号传导对调节性 T 细胞 (TREG) 至关重要，细胞因子诱导的含 SH2 蛋白 (CIS) 作为反馈抑制剂调节 IL-2R 信号传导。先前的研究确定了 CISH 启动子区域单核苷酸多态性 (SNP) 与传染病易感性的关联。年龄 < 5 年，持续时间 > 10 年）。将次要等位基因频率与 1000 基因组计划的对照队列进行比较。确定分配的单倍型对 T1D 表现和严重程度的影响。最后，在来自健康供体的 T 细胞中探索了 CISH 单倍型对细胞因子信号传导和功能的影响。结果我们在 T1D 患者和对照组之间检测到相似的次要等位基因频率。T1D 发病年龄、残留血清 C 肽水平和胰岛素需求在不同单倍型之间具有可比性。对于体外细胞因子（即IL-2、IL-7）诱导的CIS mRNA表达，仅发现单倍型之间的微小差异。STAT5 磷酸化由 IL-2 或 IL-7 诱导，但在单倍型之间没有发现差异。从具有两种最常见单倍型的健康供体中纯化的 TREG 显示出相似的抑制异源效应 T 细胞的能力。结论本研究没有提供证据表明 CISH 启动子 SNP 与 T1D 易感性或疾病严重程度之间存在关联。与以往的研究相比，