Abelson A-K, Delgado-Vega A M, Kozyrev S V, Sánchez E, Velázquez-Cruz R, Eriksson N, Wojcik J, Linga Reddy M V P, Lima G, D'Alfonso S, Migliaresi S, Baca V, Orozco L, Witte T, Ortego-Centeno N, Abderrahim H, Pons-Estel B A, Gutiérrez C, Suárez A, González-Escribano M F, Martin J, Alarcón-Riquelme M E
Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden.
Ann Rheum Dis. 2009 Nov;68(11):1746-53. doi: 10.1136/ard.2008.097642. Epub 2008 Nov 19.
To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5.
30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR.
In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis.
These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.
确认并明确信号转导与转录激活因子4（STAT4）与系统性红斑狼疮（SLE）之间的遗传关联，研究其与可变剪接和/或表达水平相关性的可能性，以及与干扰素调节因子5（IRF5）的遗传相互作用。
在一组独立的西班牙病例和对照中对30个标签单核苷酸多态性（SNP）进行基因分型。对经过多重检验校正后存活的SNP，在另外五组新的病例和对照中进行基因分型以进行重复验证。通过5'-RACE PCR和测序分析STAT4 cDNA。通过定量PCR测量表达水平。
在精细定位中，经过多重检验校正后，有四个SNP具有显著性，其中rs3821236和rs3024866信号最强，其次是先前报道的rs7574865以及rs1467199。在所有队列中均重复验证了这种关联。经过条件回归分析，由SNP rs3821236和rs7574865代表的两个主要独立信号在各数据集之间仍具有显著性。这些SNP属于不同的单倍型块。STAT4的高表达水平与rs3821236、rs3024866（二者位于同一单倍型块）和rs7574865相关，但与其他SNP无关。还检测到了选择性组织特异性外显子1的转录，这表明存在对STAT4表达可能具有重要意义的组织特异性启动子。使用回归分析未观察到与IRF5相关SNP的相互作用。
这些数据证实STAT4是SLE的一个易感基因，并提示存在至少两个影响STAT4水平的功能性变异。结果还表明，STAT4和IRF5基因以累加方式增加SLE的发病风险。
