Laboratory of Genetics, Department of Biology Enrico Calef, University of Roma Tor Vergata, Rome, Italy.
Ann Rheum Dis. 2012 Aug;71(8):1309-15. doi: 10.1136/ard.2010.147025. Epub 2012 Jan 31.
To determine whether the allelic frequency variation of the HS1.2 enhancer of the immunoglobulin heavy chain (IgH) 3' regulatory region (3'RR-1) locus represents a risk factor for systemic lupus erythematosus (SLE) and to identify a possible functional difference in the two most frequent alleles (*1 and *2) in binding nuclear factor- κB (NF-κB) and Sp1.
The frequency of the enhancer HS1.2 alleles was determined in two cohorts of patients with SLE (n=293) and in 1185 controls. Electrophoretic mobility shift assays (EMSA) were carried out with B cell nuclear extracts with different probes of HS1.2 alleles *1 and *2 to map the consensus binding sites of the nuclear factors. A confirmatory cohort of 121 patients with SLE was also included.
The frequency of allele *2 of the HS1.2 enhancer was significantly increased in patients with SLE compared with controls (OR 1.60, 95% CI 1.33 to 1.92, p<0.001). EMSA experiments showed the presence of the Sp1 binding site in both alleles whereas only allele *2 carried the consensus for the NF-κB factor. The presence versus absence of allele *2 in patients with SLE correlated with a higher concentration of IgM levels and with the expression of B cell activating factor receptor (BAFF-R).
The increased frequency of allele *2 in patients with SLE identifies a new genetic risk factor for SLE. A possible biological effect of the polymorphism could be the difference observed in the localisation of an NF-κB binding site which is specific for allele *2 and absent in allele *1. These observations suggest a functional effect of the HS1.2 enhancer in this disease.
确定免疫球蛋白重链（IgH）3'调控区（3'RR-1）位点的 HS1.2 增强子等位基因频率的变化是否代表系统性红斑狼疮（SLE）的危险因素，并确定两个最常见等位基因（*1 和 *2）在与核因子-κB（NF-κB）和 Sp1 结合方面的可能功能差异。
在两个 SLE 患者队列（n=293）和 1185 名对照中确定增强子 HS1.2 等位基因的频率。使用不同 HS1.2 等位基因 *1 和 *2 的 B 细胞核提取物进行电泳迁移率变动分析（EMSA），以绘制核因子的共识结合位点图谱。还包括一个 121 例 SLE 患者的确认队列。
与对照组相比，SLE 患者 HS1.2 增强子等位基因 *2 的频率显着增加（OR 1.60，95%CI 1.33 至 1.92，p<0.001）。EMSA 实验表明，两个等位基因都存在 Sp1 结合位点，而只有等位基因 *2 携带 NF-κB 因子的共识。SLE 患者中存在或不存在等位基因 *2 与 IgM 水平的浓度升高以及 B 细胞激活因子受体（BAFF-R）的表达相关。
SLE 患者等位基因 *2 的频率增加确定了 SLE 的新遗传危险因素。多态性的可能生物学效应可能是观察到的 NF-κB 结合位点的定位差异，该结合位点是等位基因 *2 特有的，而在等位基因 *1 中不存在。这些观察结果表明 HS1.2 增强子在该疾病中具有功能作用。
