幼年特发性关节炎与其他自身免疫性疾病共有的易感基因座延伸至蛋白酪氨酸磷酸酶非受体型2（PTPN2）、保守寡聚高尔基复合体蛋白6（COG6）和血管生成素1（ANGPT1）。
The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1.
作者信息
Thompson Susan D, Sudman Marc, Ramos Paula S, Marion Miranda C, Ryan Mary, Tsoras Monica, Weiler Tracey, Wagner Michael, Keddache Mehdi, Haas J Peter, Mueller Cornelia, Prahalad Sampath, Bohnsack John, Wise Carol A, Punaro Marilynn, Zhang Dongping, Rosé Carlos D, Comeau Mary E, Divers Jasmin, Glass David N, Langefeld Carl D
机构信息
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
出版信息
Arthritis Rheum. 2010 Nov;62(11):3265-76. doi: 10.1002/art.27688.
OBJECTIVE
To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA).
METHODS
Published autoimmune disease genome-wide association studies were reviewed, and 519 single-nucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated.
RESULTS
Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Meta-analysis results for the replicating loci included PTPN22 (rs6679677 [OR 1.58, P = 1.98 × 10(-12) ], rs2476601 [OR 1.64, P = 1.90 × 10(-13) ], and rs2488457 [OR 1.32, P = 6.74 × 10(-8) ]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 × 10(-9) ] and rs7234029 [OR 1.35, P = 1.86 × 10(-10) ]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 × 10(-6) ] and rs13143866 [OR 0.83, P = 1.95 × 10(-4) ]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 × 10(-6) ] and rs7574865 [OR = 1.31, P = 2.21 × 10(-6) ]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 × 10(-5) ]), COG6 (rs7993214 [OR = 0.76, P = 1.10 × 10(-5) ]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 × 10(-4) ]). These polymorphisms have been reported in diseases such as rheumatoid arthritis, type 1 diabetes mellitus, Crohn's disease, and multiple sclerosis.
CONCLUSION
General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms.
目的
检测先前在自身免疫性疾病中报道的非主要组织相容性复合体易感基因座与幼年特发性关节炎（JIA）之间的关联。
方法
回顾已发表的自身免疫性疾病全基因组关联研究，选择519个单核苷酸多态性（SNP）进行关联测试。初始队列包括809例JIA病例和3535名非西班牙裔欧洲血统的对照。其中，257个SNP成功进行了基因分型，168个SNP通过质量推断得出。基于初始队列的研究结果，在美国和德国收集的第二个队列中，对1015例JIA病例和1569名对照中的21个SNP进行了重复验证。对于初始队列，通过在逻辑回归模型中纳入来自全基因组关联研究的主成分作为协变量，对群体结构的潜在混杂效应进行关联测试调整。计算优势比（OR）和95%置信区间。
结果
在初始队列中对先前报道的自身免疫性疾病遗传关联进行关联测试，结果表明13个不同基因座与JIA存在关联。其中，7个在重复队列中得到验证。重复验证基因座的荟萃分析结果包括蛋白酪氨酸磷酸酶非受体型22（PTPN22，rs6679677 [OR 1.58，P = 1.98×10⁻¹²]，rs2476601 [OR 1.64，P = 1.90×10⁻¹³]，以及rs2488457 [OR 1.32，P = 6.74×10⁻⁸]）、蛋白酪氨酸磷酸酶非受体型2（PTPN2，rs1893217 [OR = 1.33，P = 1.60×10⁻⁹] 和rs7234029 [OR 1.35，P = 1.86×10⁻¹⁰]）、ADAD1-IL2-IL21（rs17388568 [OR 1.24，P = 1.13×10⁻⁶] 和rs13143866 [OR 0.83，P = 1.95×10⁻⁴]）、信号转导和转录激活因子4（STAT4，rs3821236 [OR = 1.27，P = 2.36×10⁻⁶] 和rs7574865 [OR = 1.31，P = 2.21×10⁻⁶]）、12号染色体开放阅读框30（C12orf30，rs17696736 [OR = 1.19，P = 2.59×10⁻⁵]）、高尔基复合体蛋白6（COG6，rs7993214 [OR = 0.76，P = 1.10×10⁻⁵]）和血管生成素1（ANGPT1，rs1010824 [OR = 0.79，P = 2.91×10⁻⁴]）。这些多态性已在类风湿关节炎、1型糖尿病、克罗恩病和多发性硬化症等疾病中报道过。
结论
自身免疫性疾病的一般易感基因座在包括JIA在内的多种疾病中是共享的，这表明存在共同治疗靶点和机制的可能性。
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