Polymorphisms in the vitamin D receptor gene and multiple sclerosis risk: A meta-analysis of case–control studies

Abstract

Background

The vitamin D receptor (VDR) polymorphisms have been reported to be associated with multiple sclerosis (MS), however, evidence remains conflicting. A meta-analysis was conducted to investigate this association.

Methods

We searched Pubmed, Medline and Embase databases for case–control studies evaluating the association between the VDR Apa-I, Bsm-I, Fok-I, Taq-I polymorphisms and MS risk. Data were extracted using standardized forms and odds ratios (OR) with 95% confidence intervals (CI) were calculated.

Results

11 case–control studies involving a total of 2599 cases and 2816 controls were included in this meta-analysis. Available data did not suggest an association between any of the VDR polymorphisms and the risk for MS. For Taq-I, which is the most investigated VDR polymorphism with 8 studies (2472 cases and 2446 controls), the combined OR was 1.12 (95% CI: 1.00–1.26) for the dominant model (tt + Tt vs. TT), 1.03(95% CI: 0.88–1.20) for the recessive model (tt vs. Tt + TT), and 1.04 (95% CI: 0.78–1.38) for the homozygote model (tt vs. TT). ORs for other VDR polymorphisms were similar.

Conclusion

The VDR Apa-I, Bsm-I, Fok-I and Taq-I polymorphisms are not associated with MS risk.

Introduction

Multiple sclerosis (MS) is a chronic devastating disease of the central nervous system (CNS), with a pattern of demyelination dispersed in both time and space [1]. The pathological hallmarks of the MS lesion consist of focal demyelination, inflammation, scar formation, and variable axonal destruction [2], [3]. The disease is the leading cause of non-traumatic disability in young and middle-age adults in North America and Europe. In the United States, the prevalence is 58.3 per 100,000 of the population [4]. The clinical course of MS is highly variable, usually starts with acute relapse followed by partial or complete remission, then develops into progressive and irreversible disability in later years [5], [6]. Axon loss is the major cause of irreversible disability in patients with MS [7]. It begins early and correlates with inflammatory activity. The past decade has marked the advent of various new therapeutic strategies in MS, however, these treatments are only partially effective in halting the MS disease process, and no curative therapy is available [8].

The etiology of MS is still unknown, however, it has been suggested to be affected by an interaction between genetic, environmental and geographical factors [9], [10]. Strong evidence from genetic epidemiologic studies over the past 3 decades suggests that environmental factors affect susceptibility to MS at a broad population level [11]. Even exposed to the same environment, individual susceptibility to MS may be different, which indicates that genetic factors are important in the pathogenesis of MS. Therefore, understanding the genetic basis of MS is essential for the development of therapeutic strategies. Linkage and association studies have found that the human leukocyte antigen (HLA) region is the strongest susceptibility locus for MS, but it does not completely explain the genetic impact on disease susceptibility [9]. Genes lying in non-HLA regions may also confer susceptibility for MS. In the past decade, considerable efforts and expense were put into attempts to detect the non-HLA polymorphisms contributing to the risk for MS.

Vitamin D is an important seco-steroid involved in calcium metabolism and bone formation, which also has a role in the maintenance of immune-homeostasis. Epidemiological studies have found that vitamin D deficiency is common in patients with MS [12]. The risk of MS significantly increased with decreasing serum levels of vitamin D [13]. Administration with the vitamin D bioactive form 1, 25-Dihydroxyvitamin D3 [1, 25-(OH)2D3] ameliorated the disease course and progression in experimental autoimmune encephalomyelitis (EAE), an MS animal model [14], [15]. These data suggest that limited vitamin exposure may play a role in MS. Vitamin D exerts its effects via binding to a nuclear vitamin D receptor (VDR), which is found in most cells including immune cells in the body. Engagement with vitamin D, VDR undergoes heterodimerization with the retinoid receptors, and binds to specific DNA-binding sites located in promoter regions, resulting in derepressing or coactivating the transcription of lineage-specific genes involved in calcium metabolism and immune response [16]. The VDR gene is mapped on chromosome 12q 12–14, containing 5 promoter regions, 8 protein-coding exons, and 6 untranslated exons. The existence of several restriction fragment length polymorphisms (RFLPs) in the VDR gene has been described using different restriction enzymes. Among them, Apa-I (rs7975232), Bsm-I (rs1544410), Fok-I (rs10735810) and Taq-I (rs731236) are most widely studied. Both Apa-I (C/A substitution) and Bsm-I (G/A substitution) polymorphic sites locate in the intron separating exons 8 and 9, and are without consequences for VDR protein structure [17]. Taq-I (T/C substitution) locates in exon 9 and does not cause any amino acid change in the VDR protein [18]. Fok-I (T/C substitution) locates in exon 2 and introduces an initiation code leading to the addition of three amino-acids to the VDR protein [19]. Prior studies have suggested that the VDR gene may be an important determinant of susceptibility of MS, however, the results have been inconclusive.

A single study may have low statistical power due to small sample size, unified ethnicity and other limitations, and a comprehensive analysis on different studies will provide strong evidence on the association of polymorphisms in the VDR gene and the risk for MS. Therefore, we perform this meta-analysis of all eligible studies to investigate the association between VDR gene polymorphisms and the risk for MS. This, to our knowledge, is the first meta-analysis addressing this issue.