title: Fibrinogen B beta polymorphisms do not directly contribute to an altered in vitro clot structure in humans.
abstract: Fibrinogen B beta polymorphisms, such as the -455 G/A and the Arg448Lys amino acid substitution, have been shown to increase the risk of atherothrombotic disease. Although these polymorphisms are related to fibrinogen concentrations, their effect on fibrin clot structure has not been extensively studied. We examined the frequency of the fibrinogen B beta -455 G/A polymorphism in a group of myocardial infarction (MI) patients. There was no association between this polymorphism and MI. However, we found that patients homozygous for the rare -455 A allele had a higher average age at first MI. A similar result was found for individuals homozygous for the B beta 448 Lys allele who also had a higher age at first MI. We subsequently studied the clotting properties of purified Arg448 and Lys448 fibrinogens in vitro and found that these fibrinogens did not significantly differ in their polymerisation, fibrinolysis kinetics or in their clot permeation properties. Mass spectrometry analysis of endoproteinase Asp-N digests of B beta chains revealed that the Lys(448) and the Arg(448) chains were expressed in approximately equal proportions in a heterozygote Arg448Lys individual. Our results demonstrate that the fibrinogen B beta -455 G/A polymorphism is not associated with myocardial infarction and further-more the closely linked B beta Arg448Lys protein coding variation does not have an influence on the function nor the structure of the protein in a purified system.
authors.affiliation: Molecular Pathology, Canterbury Health Laboratories, PO Box 151, Christchurch, New Zealand. ghassan.maghzal@chmeds.ac.nz
authors.forename: Ghassan J
authors.initials: GJ
authors.lastname: Maghzal
authors.forename: Stephen O
authors.initials: SO
authors.lastname: Brennan
authors.forename: Peter M
authors.initials: PM
authors.lastname: George
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation; D016022:Case-Control Studies; D005260:Female; D005337:Fibrin / Q000737:chemistry* / Q000378:metabolism; D005340:Fibrinogen / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D005342:Fibrinolysis; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D009520:New Zealand / Q000453:epidemiology; D010539:Permeability; D011110:Polymorphism, Genetic / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects
chemical_list: C115499:BBeta fibrinogen; D005337:Fibrin; D005340:Fibrinogen