The effect of a single nucleotide polymorphism on human α2-antiplasmin activity
The effect of a single nucleotide polymorphism on human α2-antiplasmin activity
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DOI：
10.1182/blood-2007-01-065185
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发表时间：
2007-06-15
期刊：
影响因子：
20.3
通讯作者：
McKee, Patrick A.
中科院分区：
文献类型：
--
作者：
Christiansen, Victoria J.;Jackson, Kenneth W.;McKee, Patrick A.
纤溶酶的主要抑制剂α（2）-抗纤溶酶（α（2）AP）由肝脏分泌到血浆中，Met作为氨基末端。在循环过程中，Met-α（2）AP被抗纤溶酶裂解酶（APCE）裂解，产生Asn-α（2）AP，Asn-α（2）AP交联成纤维蛋白的速度比Met-α（2）AP快约13倍。Met-α（2）AP基因编码Arg或Trp作为第六个氨基酸，在人血浆样品中发现两种多态形式。我们确定了健康人群中Arg 6 Trp基因型频率及其对Met-α（2）AP裂解和纤溶的影响。基因型频率RR为62.5%，RW为34.0%，WW为3.5%。与血浆Met-α（2）AP百分比相关的多态性为WW（56.4%）、RW（40.6%）和RR（23.6%）。WW血浆的裂解时间往往比RR和RW血浆短。APCE切割纯化的Met-α（2）AP（Arg 6）比Met-α（2）AP（Trp 6）快约8倍，这反映在RR、RW和WW血浆中Asn-α（2）AP/Met-α（2）AP比率随时间的变化。从血浆中去除APCE消除Met-α（2）AR的切割我们得出结论，Arg 6 Trp多态性在功能上是重要的，因为它明显影响Met-α（2）AP向Asn-α（2）AP的转化，从而影响α（2）AP掺入纤维蛋白的速率。因此，Arg 6 Trp多态性可能在控制血管内纤维蛋白的长期沉积/清除方面发挥重要作用。
The primary inhibitor of plasmin, alpha(2)-antiplasmin (alpha(2)AP), is secreted by the liver into plasma with Met as the aminoterminus. During circulation, Met-alpha(2)AP is cleaved by antiplasmin-cleaving enzyme (APCE), yielding Asn-alpha(2)AP, which is crosslinked into fibrin approximately 13 times faster than Met-alpha(2)AP. The Met-alpha(2)AP gene codes for either Arg or Trp as the sixth amino acid, with both polymorphic forms found in human plasma samples. We determined the Arg6Trp genotype frequency in a healthy population and its effects on Met-alpha(2)AP cleavage and fibrinolysis. Genotype frequencies were RR 62.5%, RW 34.0%, and WW 3.5%. The polymorphism related to the percentage of Met-alpha(2)AP in plasma was WW (56.4%), RW (40.6%), and RR (23.6%). WW plasma tended to have shorter lysis times than RR and RW plasmas. APCE cleaved purified Met-alpha(2)AP(Arg6) approximately 8-fold faster than Met-alpha(2)AP(Trp6), which is reflected in Asn-alpha(2)AP/Met-alpha(2)AP ratios with time in RR, RW, and WW plasmas. Removal of APCE from plasma abrogated cleavage of Met-alpha(2)AR We conclude that the Arg6Trp polymorphism is functionally significant, as it clearly affects conversion of Met-alpha(2)AP to Asn-alpha(2)AP, and thereby, the rate of alpha(2)AP incorporation into fibrin. Therefore, the Arg6Trp polymorphism may play a significant role in governing the long-term deposition/removal of intravascular fibrin.