The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis
The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis
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DOI：
10.1172/jci2629
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发表时间：
1998-10-01
影响因子：
15.9
通讯作者：
Woo, P
中科院分区：
文献类型：
--
作者：
Fishman, D;Faulds, G;Woo, P
在活动性疾病期间，全身性幼年慢性关节炎（S-JCA）患者血清白细胞介素-6（IL-6）的升高和降低与经典的黄热病相似。为了研究这种细胞因子谱由IL-6表达控制差异引起的可能性，我们检测了IL-6基因5'侧翼区的多态性。在-174位点检测到一个G/C多态性。在一组来自北伦敦一家全科诊所的383名健康男性和女性中，C等位基因的频率为0.403（95%置信区间为0.37-0.44）。相比之下，92例S-JCA患者的总体基因型频率不同，尤其是那些发病年龄< 5岁的患者。这主要是由于该亚组中CC基因型的频率在统计学上显著较低。当比较瞬时转染到HeLa细胞中的荧光素酶报告载体中的5'侧翼区（-550-+61bp）的构建体时，-174C构建体显示出比-174G构建体低0.624+/-0.15倍的表达。在用LPS或IL-1刺激后，与未刺激的水平相比，-174C构建体的表达在24小时后没有显著变化，而-174G构建体的表达分别增加了2.35+/-0.10-和3.60+/-0.26-倍。还测量了102名健康受试者的血浆IL-6水平，发现C等位基因与血浆IL-6水平显著降低相关。这些结果表明，个体之间IL-6对应激刺激的反应程度存在遗传决定的差异。年轻S-JCA患者中潜在保护性CC基因型的频率降低可能有助于其发病机制。类似地，个体的IL-6基因型可能与其他涉及IL-6的病症高度相关，例如动脉粥样硬化。
During active disease, patients with systemic-onset juvenile chronic arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6 (IL-6) that parallels the classic quotidian fever. To investigate the possibility that this cytokine profile results from a difference in the control of IL-6 expression, we examined the 5' flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position -174. In a group of 383 healthy men and women from a general practice in North London, the frequency of the C allele was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92 patients with S-JCA had a different overall genotype frequency, especially those with onset of disease at < 5 yr of age. This was mainly due to the statistically significant lower frequency of the CC genotype in this subgroup. When comparing constructs of the 5' flanking region (-550-+61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624+/-0.15-fold lower expression than the -174G construct. After stimulation with LPS or IL-1, expression from the -174C construct did not significantly change after 24 h, whereas expression from the -174G construct increased by 2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the unstimulated level. Plasma levels of IL-6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL-6. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young S-JCA patients may contribute to its pathogenesis. Similarly the individual's IL-6 genotype may be highly relevant in other conditions where IL-6 has been implicated, such as atherosclerosis.