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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2825-2829.)
© 1997 American Heart Association, Inc.

Articles

The Arg³⁵³Gln Polymorphism Reduces the Level of Coagulation Factor VII

In Vivo and in Vitro Studies

Mathilde Hunault; Arnaldo A. Arbini; Stanislaw Lopaciuk; Josephine A. Carew; ; Kenneth A. Bauer

From the Hematology-Oncology Section, Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.H., A.A.A., J.A.C., K.A.B.); and Laboratory of Blood Coagulation, Institute of Hematology and Blood Transfusion, Warsaw, Poland (S.L.).

Abstract Factor VII levels are regulated by environmental and genetic factors. Two polymorphisms, a G-to-A transversion at nucleotide 10976 resulting in Arg³⁵³Gln and a decanucleotide insert at position -323 in the 5'-flanking region of the factor VII gene, have been associated with a 20% to 25% reduction in plasma factor VII levels. However Arg³⁵³Gln almost always segregates on alleles containing the insert in UK and Italian populations, thereby making it impossible to independently evaluate the impact of Arg³⁵³Gln on factor VII levels in these ethnic groups. We have evaluated the influence of genotype on factor VII levels in 99 healthy Polish blood donors and observed that Arg³⁵³Gln frequently occurs in the absence of the insert. In univariate analysis, the mean levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) were significantly lower in 16 people who were heterozygous for Arg³⁵³Gln and the insert compared with 72 normal subjects who had neither Arg³⁵³Gln nor the insert (88.8% of normal and 83.1% versus 102% and 100%, P=.019 and P=.0003, respectively). In nine subjects heterozygous for Arg³⁵³Gln alone, VII:C and VII:Ag were significantly decreased compared with the normal subjects (81.9% and 83%, respectively, P=.007 and P=.004). In multivariate analysis, Arg³⁵³Gln 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 individuals with Arg³⁵³Gln, we performed transient transfection assays with factor VII cDNA containing the base substitution resulting in Gln³⁵³ 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 conclude that the Arg³⁵³Gln polymorphism alone can decrease plasma factor VII levels.

Key Words: factor VII • factor VII gene • polymorphism • triglycerides

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