Polymorphism in factor VII gene modifies phenotype of severe haemophilia

Abstract

The basis for 10-15% of patients with severe haemophilia having clinically mild disease is not fully understood. We hypothesized that polymorphisms in various coagulant factors may affect frequency of bleeding while functionally significant polymorphisms in inflammatory and immunoregulatory genes may also contribute to variations in the extent of joint damage. These variables were studied in patients with severe haemophilia, who were categorized as 'mild' (<5 bleeds in the preceding year, <10 World Federation of Haemophilia clinical and <10 Pettersson scores, n = 14) or 'severe' (all others, n = 100). A total of 53 parameters were studied in each individual for their association with the clinical severity. Age, F8:c activity and the incidence of thrombotic markers were comparable between the groups while the median number of bleeds, number of affected joints, clinical, radiological and functional joint scores (P < or = 0.001) and life-time clotting factor use (P < or = 0.007) were different. Patients with severe molecular defects had a 4.1-fold increased risk for a severe phenotype (95% CI: 1.18-14.42, P = 0.026) compared with other mutations. Of the polymorphisms studied, the FVII353Q (RR = 3.5, 95% CI: 1.04-12.05, P = 0.044) allele was associated with a severe phenotype. This data shows that apart from the F8/F9 genotype, functional polymorphisms in FVII gene affect the phenotype of patients with severe haemophilia.

Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

“…6,9,12 This is partially explained by the youngest patients in our study still being only 2.4 years of age. A few of these patients have not, as yet, had a joint bleed, and when they do, if the analysis were to be redone, the median age at first joint bleed would likely be slightly higher.…”

“…Several retrospective studies have looked at the effect of coinheritance of prothrombotic mutations, with contradictory results. 6,9,[14][15][16][17][18][19][20][21][22][23][24][25] Some studies have found that severe hemophiliacs carrying a prothrombotic mutation have a milder phenotype characterized by older age at diagnosis, 25 older age at first bleed, 15,17,26 lower annual bleeding frequency, and less arthropathy. 21,22 In contrast, other studies failed to find significant differences in severity of disease attributable to the presence of a prothrombotic mutation.…”

“…7,8 Some retrospective studies in patients with severe hemophilia treated life-long on demand have suggested that patients with F8 null mutations have a more severe phenotype than patients with F8 non-null mutations. 6,9 However, no systematic evaluation of the role of F8 genotype as a determinant of bleeding phenotype in young children with severe hemophilia A has been performed to date.…”

Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders

“…Among patients with von Willebrand disease, 1.5% were found to harbor multiple coagulopathies requiring different treatment strategies (Asatiani and Kessler 2007); secondary sites included at least seven different genes among these patients. Apparently, variations in the factor VII ( F7 ) gene can ameliorate the phenotype in severe hemophilia (A/B) resulting in a milder phenotype (Jayandharan et al 2009). …”

Fluorescent PCR-based gene dose analysis for detection of deletion mutations in carriers of haemophilia

“…Haemophilia A (HA) and haemophilia B (HB) are X-linked bleeding disorders caused by a deficiency or dysfunction of coagulation factor VIII and FIX respectively [1]. Heterogeneous mutations in either the F8 or F9 gene, including a variety of inversions, insertions, deletions and point mutations have been reported to contribute to the bleeding phenotype in patients [2][3][4]. The identification of such disease-causing mutations is important for the precise genetic diagnosis of this condition in families affected with haemophilia [1].…”