Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration

Recent studies have provided evidence for associations between common polym orphic markers in the coagulation factor VII (FVII) gene and plasma FVII le vels. Here we describe two common, nonrelated, functional polymorphisms in the promoter region of the FVII gene, a G to T substitution at position -40 1 and a novel G to A substitution at position -402, Both polymorphisms stro ngly influence the binding properties of nuclear protein(s). The rare -401T allele is associated with a reduced basal rate of transcription of the FVI I gene in human hepatoblastoma cells and with reduced plasma concentrations of total FVII (VIIag) and fully activated FVII molecules (VIIa), In contra st, the rare -402A allele confers increased transcriptional activity and is associated with increased plasma FVII levels. Together, the two polymorphi sms explained 18% and 28% of the variation in VIIag and VIIa, respectively, in a group of 183 healthy, middle-aged men. It is concluded that these pol ymorphisms are important for the regulation of the plasma levels of FVII en d that they are likely to be useful genetic markers to resolve the issue of whether a causal relationship exists between FVII levels and risk of coron ary heart disease. (C) 1999 by The American Society of Hematology.