STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk.
STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk.
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DOI：
10.1136/ard.2008.097642
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发表时间：
2009-11
影响因子：
27.4
通讯作者：
Alarcón-Riquelme ME
中科院分区：
文献类型：
--
作者：
Abelson AK;Delgado-Vega AM;Kozyrev SV;Sánchez E;Velázquez-Cruz R;Eriksson N;Wojcik J;Linga Reddy MV;Lima G;D'Alfonso S;Migliaresi S;Baca V;Orozco L;Witte T;Ortego-Centeno N;AADEA group;Abderrahim H;Pons-Estel BA;Gutiérrez C;Suárez A;González-Escribano MF;Martin J;Alarcón-Riquelme ME
为了确认和定义STAT 4与系统性红斑狼疮的遗传关联，研究与差异剪接和/或表达水平相关的可能性，以及与IRF 5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SNP进行基因分型。在5组新的病例和对照组中对经过多次检测校正后存活的SNP进行基因分型，以进行复制。STAT 4 cDNA经5 '-RACE PCR和测序分析。通过定量PCR测量表达水平。在精细定位中，四个SNP在多次测试校正后具有显著性，其中rs3821236和rs3024866是最强的信号，其次是先前相关的rs7574865和rs 1467199。在所有队列中重复了相关性。在条件回归分析后，由SNPs rs3821236和rs7574865表示的两个主要独立信号在各组中保持显著性。这些SNP属于单独的单倍型块。高水平的STAT 4表达与SNPs rs3821236、rs3024866（均在同一单倍型区块中）和rs7574865相关，但与其他SNPs无关。我们还检测到转录的替代组织特异性外显子1，表明存在组织特异性启动子的潜在重要性的STAT 4的表达。使用回归分析未观察到与IRF 5的相关SNP的相互作用。这些数据证实了STAT 4作为SLE的易感基因，并表明存在至少两种影响STAT 4水平的功能变体。我们的研究结果还表明，这两个基因STAT 4和IRF 5的行为相加，以增加SLE的风险。
To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, 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 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed 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. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. 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. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
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影响因子：
158.5
作者：
Remmers, Elaine F.;Plenge, Robert M.;Gregersen, Peter K.
通讯作者：
Gregersen, Peter K.
影响因子：
19.6
作者：
Fan, XH;Oertli, B;Wuthrich, RP
通讯作者：
Wuthrich, RP
影响因子：
--
作者：
Kozyrev, Sergey V.;Lewen, Susanna;Alarcon-Riquelme, Marta E.
通讯作者：
Alarcon-Riquelme, Marta E.
影响因子：
4.4
作者：
Singh, RR;Saxena, V;Jacob, CO
通讯作者：
Jacob, CO
影响因子：
9.8
作者：
Kyogoku, C;Langefeld, CD;Behrens, TW
通讯作者：
Behrens, TW