The study of gene-environment interactions that influence thrombosis and fibrinolysis. Genetic variation at the loci for factor VII and plasminogen activator inhibitor-1.

We describe studies on variation in the genes coding for factor VII (FVII) and plasminogen activator inhibitor-1 (PAI-1) that influence levels of these proteins in the blood. For FVII, we have identified a genetic polymorphism that results in the substitution of arginine at residue 353 to glutamine. The frequency of the glutamine allele is approximately 0.1 in samples of individuals from the United Kingdom (n = 777) and the United States (n = 140) and in Afro-Caribbeans (n = 49), and is significantly higher in a sample of individuals from the Indian subcontinent (n = 53). In all samples, carriers of the glutamine allele had levels of FVII coagulant activity 20% to 25% lower than those with only the arginine allele. These differences were highly statistically significant in the United Kingdom sample. This effect was consistent in healthy men and women and in those with coronary artery disease. In individuals homozygous for the glutamine allele, both FVII coagulant activity and antigen are low, and the mechanism of the association appears likely to be due to an effect on secretion from the liver or stability in the plasma. In individuals in the general population FVII coagulant activity is positively correlated with levels of plasma triglycerides, due to the effect of such lipoproteins on activation of FVII. This relationship appears weaker in individuals carrying the glutamine allele, and since elevated FVII coagulant antibody is associated with risk of thrombosis, this is an example of how environmental factors may interact with an individual's genotype to determine his or her thrombotic risk. Roughly 20% of the general population are carriers of the glutamine allele and are likely to be genetically protected from such risk. For PAI-1, we have recently shown that variation at the PAI gene locus, detected as DNA polymorphisms, is associated with between-individual differences in levels of PAI-1. We have now detected a common sequence change in the promoter region of the gene that explains part of this effect. The sequence change is at position 675, where a fifth guanine (5G allele) has been inserted into a run of four guanines (4G allele) when compared with published sequences. In a sample of both 83 healthy individuals and 105 young patients with coronary artery disease from Sweden, the frequency of the 4G allele is roughly 0.5, and those individuals homozygous for the 4G allele have higher levels of PAI-1 than those with other genotypes (29% higher). Preliminary data show that the 5G allele binds a hepatic nuclear protein that the 4G allele does not, suggesting that the mechanism of the effect may be due to a direct effect of the sequence change on transcription of the PAI-1 gene.(ABSTRACT TRUNCATED AT 400 WORDS)