Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk.
BACKGROUND
Polymorphisms in the fibrinogen and factor XIII genes are associated with atherothrombotic risk, but clinical studies have produced inconsistent results and laboratory studies have not explained these findings. We aimed to investigate interactions between polymorphisms in the factor XIII and fibrinogen genes, fibrinogen concentrations, and other cardiovascular risk factors in relation to fibrin structure and function.


METHODS
We used permeation analysis and electron microscopy to investigate interactions between fibrin structure, factor XIII Val34Leu, fibrinogen Aalpha Thr312Ala, fibrinogen Bbeta Arg448Lys, and fibrinogen concentrations in plasma and purified systems.


RESULTS
Increased fibrinogen concentrations were associated with decreases in permeability, with tighter clot structures in the presence of factor XIII 34Val alleles compared with those in the presence of 34Leu alleles. Findings were confirmed by scanning electron microscopy of fibrin. Similar changes in permeability were noted for Aalpha fibrinogen 312Ala compared with that for 312Thr.


CONCLUSIONS
Our results show interactions between coding polymorphisms in fibrinogen and factor XIII and fibrinogen concentrations that modify fibrin and explain the apparent paradox between epidemiological studies of factor XIII 34Leu and reported in-vitro effects on fibrin structure and function. We suggest a potential complexity of gene-gene and gene-environment interactions in determining cardiovascular risk.
Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds, UK.
Bernard C B
BC
Lim
Robert A S
RA
Ariëns
Angela M
AM
Carter
John W
JW
Weisel
Peter J
PJ
Grant
D000368:Aged; D005176:Factor XIII / Q000235:genetics*; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008855:Microscopy, Electron, Scanning; D008967:Molecular Biology; D011110:Polymorphism, Genetic; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*
D005340:Fibrinogen; D005176:Factor XIII