The effect of a single nucleotide polymorphism on human alpha 2-antiplasmin activity.
The primary inhibitor of plasmin, alpha(2)-antiplasmin (alpha(2)AP), is secreted by the liver into plasma with Met as the amino-terminus. 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)AP. 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.
Christiansen
Victoria J
VJ
William K. Warren Medical Research Center and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. victoria-christiansen@ouhsc.edu
Jackson
Kenneth W
KW
Lee
Kyung N
KN
McKee
Patrick A
PA
D019943:Amino Acid Substitution; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D000979:alpha-2-Antiplasmin / Q000235:genetics*
D000979:alpha-2-Antiplasmin; D005337:Fibrin