Department of Cardiovascular Sciences, University of Leicester, British Heart Foundation Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
J Am Coll Cardiol. 2013 Oct 8;62(15):1376-81. doi: 10.1016/j.jacc.2013.07.031. Epub 2013 Aug 7.
The study objective was to determine whether the coronary artery disease (CAD)-associated genotype at chromosome 9p21 modulates basal or induced expression of type I interferons (IFN-I).
The mechanism responsible for the association between common variants in chromosome 9p21.3 and CAD remains unclear. It has been reported that the CAD risk locus is rich in enhancer-like elements and that chromosome looping can lead to its physical proximity with the IFN-I gene cluster, raising the possibility that the locus influences CAD risk by modulating expression of IFN-Is.
We examined whether genotype at the lead CAD-associated single nucleotide polymorphism (rs1333049) in 9p21 was associated with: 1) basal levels of IFN-I in plasma from 148 healthy male subjects; 2) induction of IFN-I by Toll-like receptor stimulants in peripheral blood mononuclear cells of 60 healthy volunteers assessed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, Western blot, and IFN-I bioassay; and 3) enhancer activity of predicted IFN regulatory factor 3/7 binding sites within the 9p21 CAD risk region in reporter assays.
No significant effects of 9p21 genotype were observed for plasma levels of IFN-α, IFN-α21, or CXCL10, or leukocyte induction of IFN-α, IFN-α21, IFN-β, CXCL10, or total IFN-I measured at the mRNA, protein, and biological activity levels. There was also no enhancement of reporter activity by predicted IFN regulatory factor 3/7 binding sites in the CAD risk locus of either genotype.
The mechanism underlying the association between common 9p21 variants and CAD does not involve differential regulation of IFN-I responses.
本研究旨在确定位于 9p21 染色体上的冠心病（CAD）相关基因型是否调节 I 型干扰素（IFN-I）的基础表达或诱导表达。
导致 9p21 染色体上常见变异与 CAD 之间关联的机制尚不清楚。据报道，CAD 风险位点富含增强子样元件，染色体环化可导致其与 IFN-I 基因簇的物理接近，这增加了该位点通过调节 IFN-I 表达来影响 CAD 风险的可能性。
我们检测了位于 9p21 的 CAD 相关单核苷酸多态性（rs1333049）的基因型是否与以下方面有关：1）148 名健康男性受试者血浆中 IFN-I 的基础水平；2）60 名健康志愿者外周血单个核细胞中 Toll 样受体刺激物诱导的 IFN-I 通过酶联免疫吸附试验、定量聚合酶链反应、Western blot 和 IFN-I 生物测定评估；3）预测的 IFN 调节因子 3/7 结合位点在报告基因试验中在 9p21 CAD 风险区域内的增强子活性。
9p21 基因型对血浆 IFN-α、IFN-α21 或 CXCL10 水平或白细胞诱导的 IFN-α、IFN-α21、IFN-β、CXCL10 或总 IFN-I 的mRNA、蛋白和生物活性水平均无显著影响。两种基因型下 CAD 风险位点的预测 IFN 调节因子 3/7 结合位点也没有增强报告基因的活性。
常见 9p21 变异与 CAD 之间关联的机制不涉及 IFN-I 反应的差异调节。
