Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Sci Rep. 2018 Jul 4;8(1):10074. doi: 10.1038/s41598-018-28423-9.
To investigate whether CTLA-4 +49 G/A (rs231775), a tagSNP in Asian, is a functional T1D SNP, we genotyped this SNP with 1035 T1D patients and 2575 controls in Chinese Han population. And 1280 controls measured insulin release and sensitivity based on an oral glucose tolerance test; 283 newly diagnosed T1D patients assayed C-peptide level based on a mixed-meal tolerance test. 31 controls were analyzed for different T cell subsets by multi-color flow cytometry. Under additive model, we found that CTLA-4 +49 G/A was significantly associated with T1D (P = 2.82E-04, OR = 1.25, 95% CI: 1.12-1.41), which was further confirmed by meta-analysis (P = 1.19E-08, OR = 1.65, 95% CI: 1.38-1.96) in Chinese Han population. Although we did not find any association between this SNP and beta-cell function in either healthy individuals or newly diagnosed T1D patients, healthy individuals carrying GG/GA genotypes had lower CTLA-4 expression in naïve or activated CD4 Treg subsets (P = 0.0046 and 0.0317 respectively). A higher positive rate of IA-2A was observed among T1D patients with GG genotype compared with AA (OR = 0.51, 95% CI: 0.30-0.84, p = 0.008). Collectively, CTLA-4 +49 G/A reached a GWAS significant association with T1D risk in Chinese Han population, affects CTLA-4 expression in Treg subsets and subsequently humoral immunity in T1D patients.
为了研究 CTLA-4 +49 G/A（rs231775），亚洲的一个标签 SNP 是否是功能性 T1D SNP，我们在汉族人群中对 1035 名 T1D 患者和 2575 名对照进行了该 SNP 的基因分型。1280 名对照者进行了口服葡萄糖耐量试验以测量胰岛素释放和敏感性；283 名新诊断的 T1D 患者进行了混合餐耐量试验以测定 C 肽水平。31 名对照者通过多色流式细胞术分析了不同的 T 细胞亚群。在加性模型下，我们发现 CTLA-4 +49 G/A 与 T1D 显著相关（P = 2.82E-04，OR = 1.25，95%CI：1.12-1.41），这在汉族人群的荟萃分析中得到了进一步证实（P = 1.19E-08，OR = 1.65，95%CI：1.38-1.96）。尽管我们在健康个体或新诊断的 T1D 患者中均未发现该 SNP 与胰岛β细胞功能之间存在任何关联，但携带 GG/GA 基因型的健康个体在幼稚或激活的 CD4 Treg 亚群中的 CTLA-4 表达较低（P = 0.0046 和 0.0317 分别）。与 AA 相比，GG 基因型的 T1D 患者中 IA-2A 的阳性率更高（OR = 0.51，95%CI：0.30-0.84，p = 0.008）。总体而言，CTLA-4 +49 G/A 在汉族人群中与 T1D 风险达到了 GWAS 显著关联，影响 Treg 亚群中的 CTLA-4 表达，并随后影响 T1D 患者的体液免疫。
