CTLA-4 +49 G/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function.
CTLA-4 +49 G/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function.
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CTLA-4 49 G/A 是一种功能性 T1D 风险 SNP，影响 Treg 亚群中的 CTLA-4 水平和 IA-2A 阳性，但不影响 β 细胞功能
DOI：
10.1038/s41598-018-28423-9
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发表时间：
2018-07-04
影响因子：
4.6
通讯作者：
Yang T
中科院分区：
文献类型：
--
作者：
Chen Y;Chen S;Gu Y;Feng Y;Shi Y;Fu Q;Wang Z;Cai Y;Dai H;Zheng S;Sun M;Zhang M;Xu X;Chen H;Xu K;Yang T
为了研究在亚洲人群中作为标签单核苷酸多态性（tagSNP）的细胞毒性T淋巴细胞相关抗原4（CTLA - 4）+49 G/A（rs231775）是否是1型糖尿病（T1D）的功能性单核苷酸多态性，我们对中国汉族人群中的1035例T1D患者和2575例对照进行了该单核苷酸多态性的基因分型。并且1280例对照基于口服葡萄糖耐量试验测定了胰岛素释放和敏感性；283例新诊断的T1D患者基于混合餐耐量试验测定了C肽水平。通过多色流式细胞术对31例对照进行了不同T细胞亚群的分析。在加性模型下，我们发现CTLA - 4 +49 G/A与T1D显著相关（P = 2.82×10⁻⁴，优势比[OR] = 1.25，95%置信区间[CI]：1.12 - 1.41），在中国汉族人群中的荟萃分析进一步证实了这一点（P = 1.19×10⁻⁸，OR = 1.65，95% CI：1.38 - 1.96）。尽管我们在健康个体或新诊断的T1D患者中均未发现该单核苷酸多态性与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初始或活化的CD4调节性T细胞（Treg）亚群中CTLA - 4表达较低（分别为P = 0.0046和0.0317）。与AA基因型相比，GG基因型的T1D患者中胰岛细胞抗原2抗体（IA - 2A）的阳性率更高（OR = 0.51，95% CI：0.30 - 0.84，p = 0.008）。总之，CTLA - 4 +49 G/A在中国汉族人群中与T1D风险达到了全基因组关联研究（GWAS）显著相关，影响Treg亚群中CTLA - 4的表达，并进而影响T1D患者的体液免疫。
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.
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影响因子：
5
作者：
Chan, D. V.;Gibson, H. M.;Aufiero, B. M.;Wilson, A. J.;Hafner, M. S.;Mi, Q-S;Wong, H. K.
通讯作者：
Wong, H. K.
影响因子：
30.8
作者：
Onengut-Gumuscu, Suna;Chen, Wei-Min;Burren, Oliver;Cooper, Nick J.;Quinlan, Aaron R.;Mychaleckyj, Josyf C.;Farber, Emily;Bonnie, Jessica K.;Szpak, Michal;Schofield, Ellen;Achuthan, Premanand;Guo, Hui;Fortune, Mary D.;Stevens, Helen;Walker, Neil M.;Ward, Lucas D.;Kundaje, Anshul;Kellis, Manolis;Daly, Mark J.;Barrett, Jeffrey C.;Cooper, Jason D.;Deloukas, Panos;Todd, John A.;Wallace, Chris;Concannon, Patrick;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
8.7
作者：
Rudd CE;Taylor A;Schneider H
通讯作者：
Schneider H