THE ARG(353)GLN POLYMORPHISM REDUCES THE LEVEL OF COAGULATION-FACTOR-VII - IN-VIVO AND IN-VITRO STUDIES

Factor VII levels are regulated by environmental and genetic factors. Two polymorphisms, a G-to-A transversion at nucleotide 10976 resulting in Arg(353)Gln and a decanucleotide insert at position -323 in the 5' -flanking region of the factor VII gene, have been associated with a 2 0% to 25% reduction in plasma factor VII levels. However Arg(353)Gln a lmost always segregates on alleles containing the insert in UK and Ita lian populations, thereby making it impossible to independently evalua te the impact of Arg(353)Gln on factor VII levels in these ethnic grou ps. We have evaluated the influence of genotype on factor VII levels i n 99 healthy Polish blood donors and observed that Arg(353)Gln frequen tly occurs in the absence of the insert. In univariate analysis, the m ean levels of factor VII coagulant activity (VII:C) and factor VII ant igen (VII:Ag) were significantly lower in 16 people who were heterozyg ous for Arg(353)Gln and the insert compared with 72 normal subjects wh o had neither Arg(353)Gln nor the insert (88.8% of normal and 83.1% ve rsus 102% and 100%, P=.019 and P=.0003, respectively). In nine subject s heterozygous for Arg(353)Gln alone, VII:C and VII:Ag were significan tly decreased compared with the normal subjects (81.9% and 83%, respec tively, P=.007 and P=.004). In multivariate analysis, Arg(353)Gln but not the insert significantly reduced VII:C and VII:Ag after adjustment for age and plasma triglycerides (P<.05 and P=.02: respectively). To evaluate the mechanism responsible for reduced factor VII levels in in dividuals with Arg(353)Gln, we performed transient transfection assays with factor VII cDNA containing the base substitution resulting in Gl n(353) and wild-type factor VII cDNA in COS-1 cells. The levels of VII :Ag in the cell lysates were similar, but the amino acid substitution significantly reduced factor VII secretion into the media to 74.9% of wild-type (P=.0001). Based on these in vivo and in vitro studies, we c onclude that the Arg(353)Gln polymorphism alone can decrease plasma fa ctor VII levels.