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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3423-3428
Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies
Mirko Pinotti,
Raffaella Toso,
Domenico Girelli,
Debora Bindini,
Paolo Ferraresi,
Maria L. Papa,
Roberto Corrocher,
Giovanna Marchetti, and
Francesco Bernardi
From the Dipartimento di Biochimica e Biologia Molecolare-CIBF,
Università di Ferrara, Ferrara, Italy; the
Dipartimento di Medicina Clinica e Sperimentale, Università di
Verona, Verona, Italy; and the Centro Emofilia e Trombosi, Ospedale
Nuovo Pellegrini, Naples, Italy.
Previous studies have established that factor VII gene (F7)
polymorphisms (5'F7 and R353Q)
contribute about one-third of factor VII (FVII) level variation in
plasma. However, F7 genotyping in patients with cardiovascular
disease has produced conflicting results. Population and expression
studies were used to investigate the role of intron 7 (IVS7 ) polymorphisms, including repeat and sequence
variations, in controlling activated FVII (FVIIa) and antigen (FVIIag)
levels. Genotype-phenotype studies performed in 438 Italian subjects suggested a positive relation between the IVS7 repeat
number and FVII levels. The lowest values were associated with the
IVS7 + 7G allele. The screening of 52 patients with mild
FVII deficiency showed an 8-fold increase in frequency (8%) of this
allele, and among heterozygotes for identical mutations, lower FVII
levels were observed in the IVS7 + 7G carriers. This frequent genetic component participates in the phenotypic heterogeneity of FVII deficiency. The evaluation of the individual contribution of
polymorphisms was assisted by the expression of each IVS7
variant, as a minigene, in eukaryotic cells. The novel quantitative
analysis revealed that higher numbers of repeats were associated with
higher mRNA expression levels and that the IVS7 + 7G
allele, previously defined as a functionally silent polymorphism, was
responsible for the lowest relative mRNA expression. Taken together,
these findings indicate that the IVS7 polymorphisms contribute
to the plasmatic variance of FVII levels via differential efficiency of
mRNA splicing. These studies provide further elements to understand the
control of FVII levels, which could be of importance to ensure the
hemostatic balance under pathologic conditions.
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