The Functional Effects of the-455G/A Polymorphism on the IL-6-Induced Expression of the β-Fibrinogen Gene may be due to Linkage Disequilibrium with Other Functional Polymorphisms
The Functional Effects of the-455G/A Polymorphism on the IL-6-Induced Expression of the β-Fibrinogen Gene may be due to Linkage Disequilibrium with Other Functional Polymorphisms
复制标题
DOI：
10.1080/08820130902745153
复制
发表时间：
2009-01-01
影响因子：
2.8
通讯作者：
De Nardin, Ernesto
中科院分区：
文献类型：
--
作者：
Morozumi, Toshiya;Sharma, Ashu;De Nardin, Ernesto
血浆纤维蛋白原水平升高已被确认为冠心病、中风和外周动脉疾病的独立危险因素。β-纤维蛋白原基因启动子区-455G/A多态与血浆纤维蛋白原水平升高有关。然而，这种多态的功能效应一直存在争议，纤维蛋白原基因的其他多态也与较高的纤维蛋白原水平有关。在这项研究中，我们评估了4种天然单倍型和6种人工单倍型在β-纤维蛋白原基因启动子区域的转录活性。IL-6诱导活性在-1420A和-148T等位基因中显著降低。相反，-854A等位基因具有更高的活性。还分析了含有-1420A、-854A和-148T等位基因的人工单倍型，以证实个体功能效应。-1420A和-148T等位基因显著降低酶活性，-854A等位基因显著提高酶活性。通过本研究，我们得出结论：纤维蛋白原启动子区-1420G/A、-854G/A和-148C/T多态是功能性多态，而-455G/A多态可能不是功能性多态，-455G/A多态与较高的纤维蛋白原水平的关联实际上可能是由于-455G/A多态与其他真正的功能多态之间的连锁不平衡所致。
Elevated plasma fibrinogen levels have been identified as an independent risk factor for coronary heart diseases, stroke and peripheral artery disease. The -455G/A polymorphism in the promoter region of the beta-fibrinogen gene has been associated with increased plasma fibrinogen levels. However, the functional effect of this polymorphism has been controversial and other polymorphisms in the fibrinogen gene have also been implicated in higher fibrinogen levels. In this study, we evaluated the transcriptional activity of 4 natural haplotypes and 6 artificial haplotypes in the promoter region of the beta-fibrinogen gene. Significantly lower IL-6-induced activity was observed in the -1420A and -148T alleles. In contrast, the -854A allele had significantly higher activity. Artificial haplotypes containing the -1420A, -854A and -148T alleles were also analyzed to confirm individual functional effects. The -1420A and -148T alleles significantly lowered the activities, while the -854A allele significantly raised the activity. From this study we conclude that the -1420G/A, -854G/A and -148C/T polymorphisms in the beta-fibrinogen promoter region are functional polymorphisms while the -455G/A polymorphism may not be a functional one, and that the association of the -455G/A polymorphism with higher fibrinogen levels may actually be due to linkage disequilibrium between the -455G/A polymorphism and other truly functional polymorphisms.