Gene-environment interaction in the determination of levels of haemostatic variables involved in thrombosis and fibrinolysis.
Functional sequence changes in the promoter of a gene may have a direct effect on the rate of transcription and thus on cellular or plasma levels of the protein. For both the beta fibrinogen gene and the plasminogen activator inhibitor-1 (PAI-1) gene such functional variations have been described. For the fibrinogen gene a G/A sequence variation has been detected at position -455 of the promoter, with carriers of the A allele, representing roughly 20% of the population, consistently having 7-10% higher fibrinogen levels than those with the genotype G/G. For the PAI-1 gene we have detected a run of four or five Guanidine residues (4G/5G polymorphism), and in several published studies those homozygous for the 4G allele (25% of the population) having levels of PAI-1 roughly 30% higher levels than 5G5G individuals. The magnitude of both of these genotype effects indicates that they are likely to be of biological significance in causing an elevated risk of thrombosis and reduced fibrinolysis. However the magnitude of these effects are modulated by several environmental factors and data will be presented to demonstrate interaction between genotype and presence of ischaemic disease and physical exercise, in the determination of an individual's plasma fibrinogen levels and of triglycerides and diabetes in determining levels of PAI-1.
Humphries
S E
SE
Dept of Medicine, University College London Medical School, Rayne Institute, UK.
Panahloo
A
A
Montgomery
H E
HE
Green
F
F
Yudkin
J
J
D002874:Chromosome Mapping; D004777:Environment; D005340:Fibrinogen / Q000235:genetics; D005342:Fibrinolysis / Q000235:genetics*; D014644:Genetic Variation; D006487:Hemostasis / Q000235:genetics*; D006801:Humans; D017202:Myocardial Ischemia / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics*
D005340:Fibrinogen