Kathiresan Sekar, Yang Qiong, Larson Martin G, Camargo Amy L, Tofler Geoffrey H, Hirschhorn Joel N, Gabriel Stacey B, O'Donnell Christopher J
National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA 01702-5827, USA.
Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1405-12. doi: 10.1161/01.ATV.0000222011.13026.25. Epub 2006 Apr 13.
We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD).
In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-beta[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum P=0.002) and of 7 F7 SNPs and factor VII level (minimum P<0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in factor VII level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global P=0.0004).
A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and factor VII level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence variation and risk of CVD.
我们采用基于连锁不平衡（LD）的基因方法来研究以下假设，即5个血栓形成基因中的常见序列变异会影响血浆止血蛋白水平或心血管疾病（CVD）风险。
在一个参考样本中，我们对纤维蛋白原基因簇（纤维蛋白原β[FGB]、FGA和FGG）、凝血因子VII（F7）和组织纤溶酶原激活剂（PLAT）位点的LD结构进行了特征分析。在1811名无亲属关系的弗雷明汉心脏研究参与者中对41个标签单核苷酸多态性（SNP）进行了基因分型。9个FGB SNP与纤维蛋白原水平存在显著关联（最小P=0.002），7个F7 SNP与凝血因子VII水平存在显著关联（最小P<0.0001）。PLAT位点的SNP与PLAT水平无关。在逐步分析中，一个FGB变异解释了纤维蛋白原水平1%的残余变异，2个F7 SNP共同解释了凝血因子VII水平10%的残余变异。2种PLAT单倍型与CVD相关（多变量调整后的总体P=0.0004）。
对常见序列变异的全面调查表明，顺式调控SNP解释了循环纤维蛋白原和凝血因子VII水平中适度比例的残余变异，并且PLAT单倍型增加了CVD风险。有必要进行更多研究以证实PLAT序列变异与CVD风险之间的关联。
