Trégouet D A, Aubert H, Henry M, Morange P, Visvikis S, Juhan-Vague I, Tiret L
INSERM U525, Epidemiological and Molecular Genetics of Cardiovascular Diseases, 91 bd de l'Hôpital, 75634 Paris Cedex 13, France, Paris.
Hum Genet. 2001 Aug;109(2):191-7. doi: 10.1007/s004390100558.
By decreasing plasminogen binding to fibrin surface, the thrombin activatable fibrinolysis inhibitor (TAFI) has been hypothesized to constitute an early marker for atherothrombotic diseases. Previous studies have shown that plasma TAFI levels exhibit a high interindividual variability that is only poorly explained by lifestyle factors. Several polymorphisms of the TAFI gene have been described, and a combination of a C+1542G substitution in the 3' untranslated region and an Ala147Thr amino acid change has been shown to explain 60% of TAFI variability in a sample of unrelated individuals. A segregation-linkage analysis was performed to determine whether these polymorphisms are directly involved in the genetic regulation of TAFI levels, or whether they are only markers in linkage disequilibrium (LD) with unmeasured TAFI-linked quantitative trait loci (QTLs). The sample consisted of 97 healthy nuclear families from the Stanislas Cohort. The C+1542G and Ala147Thr polymorphisms were in complete negative LD, with minor allele frequencies of 0.27 and 0.28, respectively. Results of the segregation-linkage analysis provided evidence of two TAFI-linked QTLs in LD with the two measured polymorphisms, which would explain 78% of the TAFI variance, as compared with 55% explained by the C+1542G and the Ala147Thr polymorphisms combined. The two putative QTLs would have minor allele frequencies of 0.45 and 0.32, respectively. The hypothesis that one of the measured polymorphisms is one of the QTLs was rejected. The putative QTLs also did not seem compatible with the other TAFI gene polymorphisms that we have previously described. More extensive sequencing of the TAFI gene is necessary to identify the functional variants.
通过降低纤溶酶原与纤维蛋白表面的结合，凝血酶激活的纤溶抑制物（TAFI）被认为是动脉粥样硬化血栓形成疾病的早期标志物。先前的研究表明，血浆TAFI水平存在高度个体差异，生活方式因素对其解释能力有限。已描述了TAFI基因的几种多态性，其中3'非翻译区的C+1542G替换和Ala147Thr氨基酸变化的组合在无关个体样本中可解释60%的TAFI变异性。进行了分离连锁分析，以确定这些多态性是否直接参与TAFI水平的遗传调控，或者它们是否只是与未测量的TAFI连锁数量性状位点（QTL）处于连锁不平衡（LD）状态的标记。样本包括来自斯坦尼斯拉斯队列的97个健康核心家庭。C+1542G和Ala147Thr多态性处于完全负LD状态，次要等位基因频率分别为0.27和0.28。分离连锁分析结果提供了证据，表明存在两个与两个测量多态性处于LD状态的TAFI连锁QTL，这两个QTL可解释78%的TAFI变异，而C+1542G和Ala147Thr多态性组合可解释55%。两个假定的QTL次要等位基因频率分别为0.45和0.32。测量的多态性之一是QTL的假设被拒绝。假定的QTL似乎也与我们先前描述的其他TAFI基因多态性不兼容。需要对TAFI基因进行更广泛的测序以鉴定功能变异。
