Elsevier

Joint Bone Spine

Volume 79, Issue 2, March 2012, Pages 144-148
Joint Bone Spine

Original article
Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behçet's disease in Tunisians

https://doi.org/10.1016/j.jbspin.2011.06.003Get rights and content

Abstract

Objectives

Reports of immunomodulating effects of vitamin D suggest a need for examining allele and genotype frequencies of the vitamin D nuclear receptor gene (VDR) in patients with autoimmune diseases. T-helper-1 (Th1) counts in peripheral blood are increased in both rheumatoid arthritis (RA) and Behçet's disease (BD). We studied VDR polymorphisms in patients with these two diseases in Tunisia.

Methods

In 108 patients with RA, 131 patients with BD, and 152 controls, we studied FokI and BsmI VDR polymorphisms, using the restriction fragment length polymorphism technique.

Results

The FokI polymorphism alleles and genotype were significantly more common in the RA group than in the controls (P = 0.001 and P = 0.005, respectively). The FokI F allele and F/F genotype were significantly associated with BD (P = 0.0003 and P = 0.002, respectively). Furthermore, in the group with BD, the FokI polymorphism was significantly associated with the presence of vascular manifestations (P = 0.006). In patients with RA, the FokI polymorphism was significantly associated with female gender (P = 0.003). No significant associations were found between the Bsm1 polymorphism and RA or BD.

Conclusion

The VDR F allele is associated with RA and BD in Tunisians.

Introduction

Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, with a prevalence of 0.5 to 1% in the adult general population [1]. Females are affected three times more often than males, and onset usually occurs between 40 and 60 years of age. RA is a complex systemic autoimmune disease characterized by chronic inflammation of the synovial membrane, joint destruction, and potentially life-threatening extraarticular manifestations [2], [3], [4], [5].

RA is not related to deleterious effects of a gene mutation occurring with a low frequency in the general population. Similar to most multifactorial diseases, RA probably develops when an individual having a combination of genetic susceptibility factors is exposed to deleterious environmental influences. RA is considered to be mediated by T-helper-1 (Th1) cells. The Th1 phenotype is associated with inflammation, whereas the Th2 phenotype tends to have antiinflammatory effects. The pathogenesis of RA rests on a dual hierarchy of proinflammatory factors and autoimmunity involving both Th1 cells and the proinflammatory cytokine TNFα [6], [7]. An excess of proinflammatory cytokines with a relative deficiency in antiinflammatory cytokines creates a Th1-Th2 imbalance, which is a characteristic of many autoimmune diseases (known as Th1 diseases) including RA, diabetes mellitus, and Behçet's disease (BD). A major consequence of this Th1-Th2 imbalance is overproduction of TNFα, which initiates the cascade of events responsible for chronic inflammation and destruction of cartilage and bone.

BD is also a multifactorial condition, to which several genes may confer susceptibility. These genes have not yet been fully identified. BD is classified among the vasculitides. One hypothesis is that an infection contributes to the development of BD in individuals with genetic susceptibility factors, leading to Th1 stimulation with abnormal activity of neutrophils and endothelial cells [8]. In patients with BD, CD4+ and CD8+ T cells produce proinflammatory cytokines such as IL2, IL6, IL8, IL12, and TNFα, which are found in high concentrations in the serum. Peripheral blood Th1 counts are increased in correlation with disease activity. Th1 infiltrates are found within damaged tissues [9]. The abnormal persistence of these activated T cells within tissues may be related to protection against Fas-dependent apoptosis due to overexpression of the NF-κB transcription factor [10].

Vitamin D not only plays a major role in calcium and phosphate homeostasis, but also exerts many other biological effects, including effects on the immune system. Vitamin D modulates lymphocyte activity by diminishing immunoglobulin production by B cells, proliferation of T cells, and cytotoxic effects of natural killer (NK) cells and cytotoxic T cells (CTLs) [11]. Important effects of vitamin D include decreases in IL2 and interferon-γ production by Th1 cells. Conceivably, these effects of vitamin D may influence the pathogenesis of RA and BD. The vitamin D nuclear receptor (VDR) is found in most immune cells including antigen-presenting cells [12], CD4+ T cells, and CD8+ T cells, in keeping with vitamin D effects extending far beyond the maintenance of calcium-phosphate homeostasis. Immune cells produce a hydroxylase that can convert 25-OH-D to 1,25-OH2-D, which is the active form and a major regulator of the expression of genes involved in the proliferation, differentiation, apoptosis, and angiogenesis of normal and malignant cells. The gene on chromosome 12 that encodes the VDR (VDR) therefore exerts a crucial influence on the immune system in general and the Th1 cells in particular. Numerous VDR mutations and deletions have been identified in patients with a variety of disorders. Most of these genetic abnormalities result in a VDR that is unable to bind to 1,25-OH-D [13]. Over 63 polymorphisms have been reported. The most extensively studied VDR polymorphisms include FokI, BsmI, TaqI, and ApaI [14], which may contribute to explain observed variations in the balance of the immune system.

Heterozygosity for the FokI and BsmI polymorphisms is common, and we therefore elected to investigate these two polymorphisms. The mechanisms by which VDR variants may confer susceptibility to autoimmune diseases remains to be determined.

Section snippets

Methods

We studied 108 patients with RA, 131 patients with BD, and 152 healthy unrelated controls. The RA patients were recruited at the Mongi Slim Hospital, La Marsa, Tunisia, between November 2007 and March 2008. There were 87 women and 21 men, with a mean age of 51.5 ± 30 years. All 108 patients met American College of Rheumatology criteria for RA [15] (Table 1). Disease activity was assessed by computing the Disease Activity Score on 28 joints (DAS28) [16]. The BD patients were recruited at the

Results

Table 3 reports the distributions of the allele and genotype frequencies for the FokI and Bsm1 VDR polymorphisms in our study participants.

A significant difference was found for the FokI polymorphism (rs 10735810) between the RA group and the control group. The F allele was present in 68% of RA patients compared to 53.9% of controls and was significantly associated with RA (P = 0.001; (2 = 10.46; OR = 1.82; 95% confidence interval [95%CI] = 1.24–2.66). In addition, the FF genotype was significantly

Discussion

We investigated whether the VDR was involved in susceptibility to RA and/or BD in Tunisia. Our results constitute the first evidence that two VDR polymorphisms, FokI (rs 10735810) and Bsm1 (rs 1544410) influence susceptibility to two autoimmune diseases, RA and BD, in Tunisians. We studied 108 patients with RA, 131 patients with BD, and 152 healthy controls.

The Bsm1 VDR polymorphism was not associated with RA or BD in our Tunisian population, in keeping with an earlier study done in Hungary [20]

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgments

We are grateful to the entire staff of Slim Hospital, La Marsa, most notably Ms. A. Amari; and to the staff of the La Rabta Hospital, Tunis. This study was funded by the Tunisian Ministry of Education and Research.

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