Factor V Leiden mutation is associated with ocular involvement in Behçet disease

doi:10.1016/S0002-9394(99)00184-1

American Journal of Ophthalmology

Volume 128, Issue 3, September 1999, Pages 352-356

https://doi.org/10.1016/S0002-9394(99)00184-1 Get rights and content

Abstract

PURPOSE:

Behçet disease is a systemic disease of young adults characterized by venous occlusion in both the deep venous and retinal circulations. In severe ocular disease, blindness may occur despite immunosuppressive treatment. The most common inherited risk factor for the development of idiopathic venous thrombosis is the presence of the Factor V (FV Leiden) mutation, which confers resistance to activated protein C. The association of FV Leiden with Behçet disease has been reported, but its influence on ocular disease is not known. We therefore investigated the prevalence of this mutation in patients with Behçet disease to determine its contribution to the presence and severity of ocular disease.

METHODS:

One hundred and six Middle Eastern patients satisfying international criteria, and 120 healthy control subjects without a history of venous thrombosis were included in the study, and patients underwent standard examination by two ophthalmologists with an interest in Behçet disease. Genomic DNA was extracted from peripheral blood leukocytes and screened for the FV Leiden mutation with the polymerase chain reaction method with sequence-specific primers (PCR-SSP).

RESULTS:

FV Leiden was detected in 19% (23/120) of the control population compared with 27% (29/106) of all patients with Behçet disease (P = .13). However, among patients with Behçet disease who had ocular disease (75/106), the prevalence of FV Leiden was significantly higher (32%) than it was in control subjects (P = .04). Furthermore, ocular patients with Behçet disease in whom retinal occlusive disease was observed (25/75) had the highest expression of FV Leiden (44%).

CONCLUSIONS:

These data suggest that FV Leiden may be an additional risk factor for the development of ocular disease and, in particular, retinal vaso-occlusion, and it may contribute to the poor visual outcome in these patients.

Section snippets

Patients and methods

This multicenter study included 106 patients of Palestinian or Jordanian descent with Behçet disease and 120 ethnically matched unrelated control subjects who did not have Behçet disease. All patients fulfilled the international criteria for Behçet disease, and local control subjects were recruited from hospital staff. Patients were recruited and examined at the St John Ophthalmic Hospital in Jerusalem and the Jordan Hospital and King Hussein Medical Center in Amman. DNA was prepared from

Results

One hundred and six patients and 120 healthy control subjects were included in the study. Seventy-five patients (71%) had clinical evidence of previous ocular disease, and 31 patients (29%) had no evidence of ocular disease (Table 1). There was no significant difference between the ages of the ocular patients (mean age, 31.9 ± 9.2 years) and nonocular patients (mean age, 35.2 ± 11.1 years).

The Factor V Leiden mutation was detected in 29 (27.4%) of 106 patients with Behçet disease, which was

Discussion

Our study demonstrated an association between the FV Leiden mutation and ocular involvement in Behçet disease. In contrast to two previously reported associations between Behçet disease and FV Leiden,20, 21 the mutation was not significantly raised in our patients as a group compared with control subjects. This may reflect the high control FV Leiden prevalence in this ethnic group compared with Germany (8.5%), Iceland (6.2%), and African-American women (0.4%).10, 11, 18 Indeed our control FV

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Cited by (76)

The impact of the IL-1β, IL-1Ra, IL-2, IL-6 and IL-10 gene polymorphisms on the development of Behcet's disease and their association with the phenotype
2016, Medicina Clinica
Citation Excerpt :
Due to the increased inflammation occurring in BD the polymorphisms, or the mutations of the genes involved in the mechanism of inflammation, are considered to be potentially effective in the development of the disease. The studies on etiopathogenesis reported results, establishing an association between several cytokine genes and the gene polymorphisms significantly involved in the immune response, and the BD; and a hypothesis was developed that these could have an important role in the onset and course of the disease.5–9,12 We did not detect a correlation between the IL-1β gene polymorphism and the presence of BD in our trial.
This trial was designed to investigate the effects of the interleukin (IL)-1β, IL-1Ra, IL-2, IL-6, IL-10 gene polymorphisms on Behcet's disease (BD) occurrence and the association between the polymorphisms and the phenotype.
The study population consisted of 71 patients and 70 age and gender-matched healthy subjects. Each of the participants had 2cc of blood withdrawn, which was placed into a whole blood tube, and the DNA was obtained using the NucleoSpin^® Blood DNA Isolation kit. To display the band lengths, the products were amplified using the primary pairs of the interleukins investigated and developed in a 2% agarose gel.
There were no significant differences between the groups with respect to the IL-1Ra, IL-1β, IL-2, IL-6 and the IL-10 gene polymorphism distributions. In the patient group the IL-1RN2 gene polymorphism was detected to be statistically correlated with the presence of articular involvement (p = 0.0283) and the IL-1β gene polymorphism was statistically correlated with the presence of an ocular lesion (p = 0.0178). The evaluation of the IL-2 gene polymorphism (p = 0.0065) and IL-10 gene polymorphism (p = 0.0483) distributions with respect to age of BD onset revealed a statistically significant distribution.
The statistical correlations between the articular involvement and IL-1RN, the ocular involvement and the IL-1β, and the age of disease onset and the IL-2 and IL-10 gene polymorphisms, detected for the first time in the literature, suggest that these polymorphisms could be statistically associated with the disease symptoms and used as prognostic factors.
Este estudio fue designado para investigar los efectos de los polimorfismos genéticos de interleucina (IL)-1β, IL-1Ra, IL-2, IL-6 e IL-10 en la ocurrencia de la enfermedad de Behcet (EB) y la asociación entre los polimorfismos y el fenotipo.
La población de estudio consistió en 71 pacientes y 70 sujetos sanos emparejados por edad y sexo. A cada participante se le extrajeron 2cc de sangre y el ADN se obtuvo usando el kit NucleoSpin^® Blood DNA Isolation. Para mostrar las longitudes de las bandas, los productos fueron amplificados usando los primeros pares de las IL investigadas y se desarrollaron en un gel de agarosa al 2%.
No hubo diferencias significativas entre los grupos en relación con las distribuciones de los polimorfismos genéticos de IL-1Ra, IL-1β, IL-2, IL-6 e IL-10. En el grupo de pacientes, el polimorfismo genético de IL-1RN2 detectado se correlacionó estadísticamente con la presencia de afección articular (p = 0,0283), y el polimorfismo genético de IL-1β se correlacionó estadísticamente con la presencia de lesión ocular (p = 0,0178). La evaluación de la distribución del polimorfismo genético de IL-2 (p = 0,0065) e IL-10 (p = 0,0483) en relación con la edad de inicio de la EB reveló una distribución estadísticamente significativa.
La correlación estadística entre afección articular e IL-1RN, afección ocular e IL-1β, y la edad de inicio de la enfermedad y los polimorfismos genéticos de IL-2 e IL-10, detectados por primera vez en la literatura médica, evidencian que estos polimorfismos se asociaron estadísticamente a los síntomas de la enfermedad y se podrían usar como factores pronósticos.
Association of allelic variants of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase with thrombosis or ocular involvement in Behçet's disease: A systematic review and meta-analysis
2013, Autoimmunity Reviews
Thrombosis is frequent in patients with Behçet's disease (BD), although the exact cause remains uncertain. Some single nucleotide polymorphism (SNP) (G1691A in factor V gene, also called factor V Leiden [FVL], G20210A in prothrombin gene and C677T in methyltetrahydrofolate reductase [MTHFR] gene) have been associated with thrombosis and ocular involvement in BD with controversial results.
To assess the effects of FVL, prothrombin and MTHFR SNP variants in patients with BD and thrombosis and ocular involvement by means of a systematic review and meta-analysis.
We retrieved studies analyzing the genotype of the above-mentioned polymorphism among patients with BD. A meta-analysis was conducted in a random effects model and calculations of odds ratio (OR) and confidence intervals (CI) were done. Sensitivity analysis and tests for heterogeneity of the results were performed.
27 previous studies analyzed the association of BD and thrombosis with the FVL, prothrombin and MTHFR polymorphisms. A significant association was found between the possession of the AA or GA genotypes of FVL polymorphism among patients with BD and the presence of any thrombosis (OR = 2.51; 95% CI: 1.68, 3.74; P < 0.00001). In addition, a significant association was found between the possession of the GA or AA genotypes and the presence of BD (OR = 2.67; 95% CI: 1.93. 3.72; P < 0.00001) when cases with BD and healthy controls were compared. This association was not found when studies from Turkey were excluded. No association was found between prothrombin and MTHFR SNPs and thrombosis in BD, and no association between any SNP and ocular involvement was shown either.
Factor V Leiden could be responsible for some thrombotic events in at least Turkish patients. However, this relationship has to be demonstrated from a pathogenic point of view.
New insights into the pathogenesis of Behçet's disease
2012, Autoimmunity Reviews
Citation Excerpt :
In large studies, no difference was found according to the different prothrombotic factors (i.e. factor V leiden, prothrombin G20210A polymorphism, MTHFR C677T polymorphism, factor VIII, and homocysteine level) between BD patients with or without thrombosis [262,263]. Some study showed an increase risk of thrombosis among BD when factor V leiden or G20210A mutations were present whereas other studies failed to confirmed the association [263–266]. Many studies have investigated the putative role of homocysteinemia in the thrombotic risk of BD.
Behçet's disease (BD) is a recurrent systemic inflammatory disorder of unknown origin characterized by oral and genital mucous ulcer, uveitis, and skin lesions. Involvement of large vessels, central nervous system (CNS), gastrointestinal tract and thrombotic events are less frequent but can be life threatening. The aim of this review is to provide new insights into the pathogenesis of BD. Over the past year substantial advances have been done in the understanding of the genetic [1,2] and immunology [3] of BD. BD is at the crossroad between autoimmune and autoinflammatory syndromes. In common with autoimmune diseases BD shares class I MHC association. However, in contrast to autoimmune disorders, BD has clinical features that seem to be mostly autoinflammatory. The pathogenesis of BD is still unknown, but major determinants of the genetic and immune system abnormalities have been reported recently. Triggering infectious factors are supposed to participate in the outbreak of BD in genetically predisposed patients. Two recent large genome-wide association study (GWAS) conducted in Turkey and Japan reported association between single nucleotide polymorphism (SNP) of interleukin (IL)-10 and IL-23R/IL-12RB2 genes and BD. New insights into the perturbations of T cell homeostasis of BD recently emerged. We have recently demonstrated the promotion of Th17 responses and the suppression of regulatory T cells (Tregs) that were driven by interleukin (IL)-21 production and that correlates with BD activity. Inflammatory cells within BD inflammatory lesions included mostly neutrophils, Th1 and Th17 cells, and cytotoxic CD8+ and γδ T cells. Altogether, the recent progresses in the knowledge of BD pathogenesis pave the way for innovative therapy.
Study of thrombophilia factors in Italian patients suffering from Behçet disease
2010, Revue du Rhumatisme (Edition Francaise)
La maladie de Behçet (MB) peut se compliquer de thrombose artérielle et veineuse. L’objectif de ce travail a été d’évaluer dans un groupe de patients italiens atteints de MB avec évènements thrombotiques, un large panel de facteurs thrombophiliques héréditaires et acquis.
Trente patients atteints de MB, parmi lesquels neuf avaient des antécédents de thrombose artérielle ou veineuse et 21 n’en avaient pas, ont eu les examens suivants : activité antithrombine plasmatique, activité de la protéine C, taux de la protéine S libre, sensibilité à la protéine C activée (APC), concentration en homocystéine totale plasmatique, taux de folates sériques, présence d’anticorps antiphospholipides, taux sériques de Lp(a), recherche de polymorphismes pour les gènes du facteur V Leiden, de la prothrombine et de la méthylène tétrahydrofolate réductase. La recherche de polymorphismes génétiques a également été réalisée dans le groupe de patients sains.
Les six patients qui avaient des antécédents de thrombose artérielle ou veineuse profonde avaient des facteurs thrombophiliques, tels qu’un déficit en protéine C ou S (un cas chaque), une hyperhomocystéinémie (deux cas), la présence d’anticorps antiphospholipides associée à une résistance à l’APC ou à une hyperhomocystéinémie (un cas chaque). Parmi les trois sujets qui ont eu des antécédents de thrombophlébite superficielle, seul un avait une hyperhomocystéinémie modérée. Aucune différence n’a été trouvée entre les patients atteints de MB et les sujets témoins pour les polymorphismes des gènes évalués. Parmi les patients atteints de MB, la mutation H1299R du facteur V était faiblement associée à la thrombose veineuse (p : 0,048).
Chez les patients atteints de MB, la présence concomitante de différents facteurs de risque thrombophiliques pourrait contribuer au développement d’évènements thrombotiques. Les patients atteints de vasculo-Behçet devraient être évalués pour la présence de facteurs coexistents majeurs de thrombophilie.
A study on thrombophilic factors in Italian Behcet's patients
2010, Joint Bone Spine
Behcet's disease (BD) may complicate with arterial and venous thrombosis. The purpose of this work is to evaluate in an Italian group of BD patients with thrombotic events a large panel of inherited and acquired thrombophilic factors.
Thirty BD patients, of which nine with previously arterial or venous thrombosis and 21 without, underwent the following investigations: plasma antithrombin activity, protein C activity, free protein S level, sensitivity to APC, total plasma homocysteine concentration, serum folate level, determination of anti-phospholipid antibodies, serum Lp(a) levels, tests for gene polymorphisms of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase genes. Tests for the gene polymorphisms were also performed in a group of healthy control subjects.
All the six patients with arterial or deep venous thrombosis showed thrombophilic conditions such as protein C or protein S deficiency (one case each), hyperhomocysteinemia (two cases), positivity of anti-phospholipid antibodies associated with APC resistance or hyperhomocysteinemia (one case each). Among three subjects with superficial thrombophlebitis only one showed a mild hyperhomocysteinemia. No differences were found between BD patients and control subjects concerning polymorphisms of the genes considered. Among BD patients the Factor V H1299R mutation showed a weak association with venous thrombosis (P = 0.048).
In BD patients different concomitant significant thrombophilic risk factors may contribute to the development of thrombotic events. Patients affected by vasculo-Behcet should be evaluated for the presence of coexisting major thrombophilic conditions.
Vascular Behçet syndrome: from pathogenesis to treatment
2023, Nature Reviews Rheumatology

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^☆: This project was supported by the St John Ophthalmic Hospital in East Jerusalem and the Jordan Hospital in Amman, Jordan. Funding was provided by the TFC Frost Charitable Trust and the Iris Fund for the Prevention of Blindness.

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Original ArticlesFactor V Leiden mutation is associated with ocular involvement in Behçet disease☆

Abstract

Section snippets

Patients and methods

Results

Discussion

Lancet

Blood

Blood

Ophthalmology

Behçet’s disease

Studies on prognosis and symptoms of Behçet’s disease in long-term observation

Jpn J Clin Ophthalmol

Vascular involvement in Behçet’s diseasearterial and venous and vessels of all sizes

J Rheumatol

Bilateral central retinal vein occlusion in Behçet’s disease

Clin Rheumatol

Coagulation and fibrinolytic activity in Behçet’s disease

Thromb Haemost

Protein C and protein S activities in Behçet’s disease as risk factors of thrombosis

Int J Dermatol

Mutation in blood coagulation factor V associated with resistance to activated protein C

Nature

Original Articles
Factor V Leiden mutation is associated with ocular involvement in Behçet disease☆