Complexity of the genetic contribution to factor VII deficiency in two Spanish families: clinical and biological implications

Abstract

BACKGROUND AND OBJECTIVES: Although many F7 DNA variants have been described to be associated with alterations in factor VII (FVII) levels, the correlation of functional levels of FVII with disease (i.e. bleeding) is highly variable indicating that other factors are likely involved in producing this phenotype. DESIGN AND METHODS: We studied two unrelated Spanish families, identified from two asymptomatic propositi with FVII:C levels lower than 1% and 3%. Family members showed a wide range of FVII:C levels. Amplification and direct DNA sequencing of the F7 (promoter, exons, 3'-UTR and a large proportion of introns) identified the genetic variants involved. RESULTS: We characterized 3 mutations in the F7 coding region (homozygous Q100R in one patient, and double heterozygosity for M298I and G331S in another patient). We also found 16 new DNA polymorphisms. The high variability of FVII levels in family members with the same mutation shows that the inheritance of FVII phenotypes is extremely complex and suggests that polymorphisms might play an important role in modulating FVII levels, and ensuring hemostatic balance under pathologic conditions. INTERPRETATION AND CONCLUSIONS: These results highlight the importance of a concerted effect of multiple genetic factors in determining FVII levels. Since there is evidence that FVII levels constitute a risk factor for coronary heart disease and considering the importance of F7 DNA polymorphisms in determining FVII levels, further analyses of these polymorphisms should yield information to aid the understanding of the quantitative variation in FVII levels and the relative genetic risk for cardiovascular disease in the general population.