Statistics from Altmetric.com
The factor V Leiden (FV Leiden) mutation causes resistance to activated protein C by substituting the Glu506 residue with arginine at the cleavage site for activated protein C. Heterozygous carriers of the FV Leiden mutation have an increased risk of venous thrombosis between threefold and sevenfold in population based and family studies.1,2 Behçet’s disease is a chronic inflammatory multisystem disorder that affects young adults. The principal cause of visual loss in this disease is recurrent retinal vein occlusion probably due to a combination of retinal vasculitis and thrombus formation. Thrombosis in Behçet’s disease carries a poor ocular and systemic prognosis, so the presence of an identifiable and significant risk factor could be an indicator for anticoagulant treatment.3 Two recent studies have implicated FV Leiden in the pathogenesis of thrombosis in Turkish patients with Behçet’s disease. In one study, 30% of patients with Behçet’s disease complicated by thrombosis were heterozygous or homozygous for factor V Leiden compared to 5.9% of factor V Leiden negative patients.4 In the second study, factor V Leiden was detected in 37.5% of patients with Behçet’s disease and a thrombotic history, compared to 9.4% of non-thrombotic patients.5 We have previously shown in a study of 106 Middle Eastern patients with Behçet’s disease and 120 racially matched controls that the prevalence of factor V Leiden was significantly higher among patients with ocular inflammation (odds ratio 1.67) and was even more prevalent in patients who had developed retinal vascular occlusive disease (odds ratio 2.57).6
In this current study we analysed the association between factor V Leiden and clinical features of Behçet’s disease in white patients from the United Kingdom. The results show that, unlike Middle Eastern Behçet’s disease patients, factor V Leiden was not associated with Behçet’s disease in UK patients.
DNA samples from 53 white patients with Behçet’s disease were collected from individuals attending the Behçet’s disease clinic at the Medical Eye Unit, St Thomas’s Hospital, London. All patients fulfilled the international criteria for Behçet’s disease. Middle Eastern and Afro-Caribbean patients were excluded from this study. A total of 150 white controls from the London area were provided from our DNA bank. Patients’ clinical details were recorded following full systemic and ocular examination, the diagnosis of retinal vein occlusion being recorded following fluorescein angiography.
Factor V Leiden analysis
HLA typing and detection of the FV Leiden mutation was performed using PCR-SSP as previously described.6 The results were analysed by generating two by two contingency tables and statistical analysis was performed using χ2 test.
Fifty three patients (28 males, 25 female) were analysed; 74% (n=39) had ocular disease, 11 had no ocular disease, and for three patients the ocular disease status was unknown. Of those patients with ocular disease, 54% (21/39) had retinal vein occlusion.
Twenty two of 53 (42%) were HLA-B*51+ of whom 3/22 (14%) were B*5108, the remainder being B*5101 (Table 1).
Only 2/53 (3.8%) patients in this cohort of patients with Behçet’s disease were heterozygous for the FV Leiden mutation (Table 1). Both patients were male, and had ocular disease, however only one of these individuals had evidence of retinal occlusion.
The factor V Leiden mutation has been linked with ocular disease in Middle Eastern patients with Behçet’s disease, in particular those with proved retinal venous thrombosis. The current data on UK patients with Behçet’s disease do not show a similar association. The prevalence of FV Leiden in the patient group was no different from the control group. Moreover, while both patients positive for FV Leiden had ocular disease this is against a background of a high level of eye disease in this group.
There are several possibilities that could explain the difference between the two groups. Firstly, the presence of FV Leiden in the Middle Eastern population was particularly high (17%) and this may have accounted for the functional role of this molecule in retinal venous thrombosis in this ethnic population. By comparison, the low prevalence of the mutation in white people suggests that much larger numbers of Behçet’s disease patients will need to be tested to identify any possible association. This has been supported by studies on other European patients with Behçet’s disease where FV Leiden was not identified as a risk factor for systemic venous thrombosis.7 Moreover, in our previous study, we identified several patients who were homozygous for the FV Leiden mutation and were clinically blind. In a population with such a high prevalence of the mutation, homozygosity will be more common and may have biased the data in favour of an association between FV Leiden and severity of ocular disease in the patient group.6
Secondly, recent studies in relatives of individuals with venous thrombosis have shown that the presence of FV Leiden adds only a threefold risk of thromboembolism. Over half of these events were linked to other risk factors such as pregnancy, surgery, or oral contraceptives.8 This would suggest that in the general white population genetic mutations affecting proteins involved in the coagulation cascade might only be associated with thrombosis in individuals with concurrent risk factors.
Thirdly, population specific phenotypic effects have been described for other gene polymorphisms. In a worldwide survey of HIV+ and HIV individuals, a particular haplotype of the RANTES gene was associated with increased risk of acquiring HIV-1, and accelerated disease progression, in European Americans, but not African-Americans. A second RANTES haplotype was associated with delayed progression of disease in Japanese patients, but not in other ethnic groups of patients, probably because this haplotype is rarely found in non-Far East Asians.9 There are several other factor V gene polymorphisms that may be involved in white patients and these could be an area for future study.
These results suggest that interindividual and interpopulation specific genotypes are associated with disease although the phenotypic outcome remains the same. Therefore gene polymorphisms that associate with disease in one population cannot be regarded as associating with the disease in different ethnic groups. It may not be possible to identify genes involved in severity of a complex disease such as Behçet’s disease, which will hold across different patient populations.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.