Polymorphisms of coagulation/fibrinolysis genes: gene environment interactions and vascular risk.
Circulating concentrations of plasminogen activator inhibitor-1 (PAI-1), factor VII and fibrinogen have all been related to vascular risk in large prospective studies. Evidence indicates that all three proteins are increased in the presence of insulin resistance and factor VII and PAI-1 correlate strongly with circulating levels of insulin and lipids. Polymorphisms of the genes coding for PAI-1, factor VII and fibrinogen have been investigated in relation to gene environment interactions and vascular risk. Three polymorphisms have been described in the PAI-1 gene, a 3' Hind III RFLP, an intronic CA repeat and a 4G/5G insertion deletion 675 bp 5' of the start site of transcription. The 4G/5G site has been shown to be triglyceride responsive and higher levels of PAI-1 have been reported in subjects homozygous for the 4G allele. Three out of four case control studies have related possession of the 4G/4G genotype to an increased risk of coronary artery disease and our studies in patients undergoing coronary angiography indicate that this is due to increased myocardial infarction rather than atheroma. We have investigated 600 subjects with cerebrovascular disease and found no relationship to the 4G/5G polymorphism. Two major polymorphisms have been identified in the factor VII gene, a promoter decanucleotide repeat and a G-A substitution at codon 353. Evidence indicates that the latter mutation affects factor VII levels by interfering with intracellular processing of the molecule and subjects homozygous for the adenine genotype (M2/M2) have levels of factor VII 20-30% lower than M1/M2 or M1/M1 carriers. Two studies have, however, failed to show a relationship between genotype and cardiovascular disease and we have found no association with cerebrovascular disease. A number of mutations have been described in the genes coding for the alpha, beta and gamma chains of fibrinogen. These polymorphisms are reported to be responsible for from 3% to 50% of circulating levels in various studies and there is evidence that the effect of smoking is genotype specific. In the ECTIM study the beta Bcl I polymorphism has been related to cardiovascular disease and work from our unit has related the Bbeta448 polymorphism to the presence of cerebrovascular disease in women. Further prospective studies are warranted to evaluate the role of these genes in disease.
Grant
P J
PJ
Unit of Molecular Vascular Medicine, Research School of Medicine, Leeds General Infirmary, University of Leeds, UK.
D001777:Blood Coagulation / Q000235:genetics*; D002874:Chromosome Mapping; D004777:Environment; D005167:Factor VII / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014652:Vascular Diseases / Q000097:blood / Q000235:genetics*
D017395:Plasminogen Activator Inhibitor 1; D005167:Factor VII; D005340:Fibrinogen