PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity
PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity
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DOI：
10.1210/jc.2017-02577
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发表时间：
2018-05-01
影响因子：
5.8
通讯作者：
Kahaly, George J.
中科院分区：
文献类型：
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作者：
Houcken, Juliane;Degenhart, Christina;Kahaly, George J.
背景：不同基因的单核苷酸多态性（SNPs）增加了单腺自身免疫的易感性。目的：评价8个单核苷酸多态性（SNPs）与自身免疫性多腺体综合征（APS）的潜在关联，研究地点：学术转诊内分泌门诊，患者：共543例APS和单腺体自身免疫患者及对照，干预：SNP蛋白酪氨酸磷酸酶非受体22型（PTPN 22）rs 2476601（+1858）;细胞毒性T淋巴细胞相关抗原4（CTLA-4）rs3087243（CT60）和rs 231775（AG 49）;维生素D受体（VDR）rs 1544410（Bsm I）、rs7975232（阿帕I）、rs731236（Taq I）;结果：PTPN 22 + 1858等位基因和基因型在APS、1型糖尿病患者中的分布差异有统计学意义（OR：2.67; 95%置信区间（CI）：1.52至4.68; P = 0.001]、Graves病（GD; OR：1.94; 95% CI：1.16至3.25; P= 0.011）和对照组（OR：3.31，95% CI：1.82至6.02; P < 0.001）。T等位基因携带者发生APS的危险性增加（OR：3.76，95% CI：1.97 ~ 7.14，P < 0.001）。APS组T等位基因频率高于对照组（OR：3.25; 95% CI：1.82 - 5.82; P < 0.001）、T1 D组（OR：2.54; 95% CI：1.48 - 4.36; P = 0.001）或GD组（OR：1.89; 95% CI：1.15 - 3.11; P = 0.012）。SNP CTLA-4 CT60 G等位基因携带者在APS中的频率（85%）高于对照组（78%）（OR：1.55; 95%CI：0.81至2.99）。CTLA-4 AG 49和CT60的联合分析显示，APS与对照组相比，AG/GG基因型组合的OR为4.89; 95%CI：1.86至13.59; P = 0.00018。VDR基因多态性Bsm 1、阿帕1和Taq I与APS无关，但APS与对照组之间的单倍型存在差异（P = 0.0011）。
Context: Single nucleotide polymorphisms (SNPs) of various genes increase susceptibility to monoglandular autoimmunity. Data on autoimmune polyglandular syndromes (APSs) are scarce.Objective: Evaluate potential associations of eight SNPs with APSs.Setting: Academic referral endocrine clinic.Patients: A total of 543 patients with APS and monoglandular autoimmunity and controls.Intervention: The SNP protein tyrosine phosphatase nonreceptor type 22 (PTPN22) rs2476601 (+1858); cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49); vitamin D receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I); tumor necrosis factor a rs1800630 (-863); and interleukin-2 receptor alpha rs10795791 were tested by single-base extension in all subjects.Results: The PTPN22 +1858 allele and genotype distribution were markedly different between APS, type 1 diabetes [T1D; odds ratio (OR): 2.67; 95% confidence interval (CI): 1.52 to 4.68; P = 0.001], Graves disease (GD; OR: 1.94; 95% CI: 1.16 to 3.25; P= 0.011), and controls (OR: 3.31, 95% CI: 1.82 to 6.02; P < 0.001). T-allele carriers' risk for APS was increased (OR: 3.76; 95% CI: 1.97 to 7.14; P < 0.001). T-allele frequency was higher among APS than controls (OR: 3.25; 95% CI: 1.82 to 5.82; P < 0.001), T1D (OR: 2.54; 95% CI: 1.48 to 4.36; P = 0.001), or GD (OR: 1.89; 95% CI: 1.15 to 3.11; P = 0.012). The SNP CTLA-4 CT60 G-allele carriers were more frequent in APS (85%) than controls (78%) (OR: 1.55; 95% CI: 0.81 to 2.99). Combined analysis of CTLA-4 AG49 and CT60 revealed OR 4.89; 95% CI: 1.86 to 13.59; P = 0.00018 of the genotype combination AG/GG for APS vs controls. VDR polymorphisms Bsm 1, Apa 1, and Taq I did not, but the haplotypes differed between APS and controls (P = 0.0011).Conclusions: PTPN22 and CTLA-4 polymorphisms are associated with APS and differentiate between polyglandular and monoglandular autoimmunity.