Preliminary ReportAssociations of Vitamin D Receptor Single Nucleotide Polymorphisms with Susceptibility to Systemic Sclerosis
Introduction
Systemic sclerosis (SSc, scleroderma) is a severe autoimmune disease that is characterized by vascular abnormalities, immunological alterations and fibrosis of the skin and internal organs (1). Based on the extent of skin involvement, SSc is classified into limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) scleroderma. The overall incidence rates of SSc range globally from 8 to 56 new cases/million/year, which is observed predominantly in females. Although the pathogenesis of SSc is not yet fully clarified, genetic and environmental factors are implicated in disease susceptibility (2,3).
Vitamin D (VD) is a necessary micronutrient for human beings, and plays an important role in the bone health and calcium homeostasis (4). VD deficiency impairs immune responses and self-tolerance by compromising the functions of these cells including natural killer cells, T or B lymphocytes. Accumulating evidence indicates that VD deficiency could contribute to the risk of autoimmune diseases such as SSc (5). Actually, VD has several immunomodulatory effects mediating them through binding to its specific receptor, vitamin D receptor (VDR), existing in most cell types of the immune system, mainly antigen-presenting cells and T cells, which belongs to the superfamily of transacting transcriptional regulatory factors (6). Notably, VDR activation plays a central role in modulating the immunological response. Specific variants of the VDR gene are associated with alterations in VD function and metabolism (7,8). These results suggest VDR gene may be related to autoimmunity diseases susceptibility including SSc.
In humans, the VDR gene is located on chromosome 12q13.11., extends over 100 kb and includes eight protein-coding exons, six untranslated exons, eight introns and two promoter regions, with numerous single nucleotide polymorphisms (SNPs) (9,10). Associations between VDR polymorphisms and susceptibility to autoimmunity diseases have been conducted in different settings and ethnic backgrounds, while the results obtained so far are conflicting (11, 12, 13, 14, 15). On the contrary, a meta-analysis was conducted on the associations between the VDR gene polymorphism and rheumatoid arthritis (RA) or SLE, which found that the BsmI polymorphism was significant risk factors for SLE and the FokI polymorphism may confer susceptibility to RA in Europeans (13). Notably, there is still a scarcity of data regarding the association of VDR SNPs with SSc patients. To our knowledge, there was only one study explored that the association between VDR gene polymorphisms and SSc in the Egyptian population, but the samples sizes was small (30 cases and 60 controls) and only two common VDR polymorphisms (ApaI and TaqI) were analyzed (16). Unfortunately, the possible relationship between SSc and VDR SNPs in Chinese Han population still remains uncertain.
Thus, in the current study, to clarify whether the VDR gene polymorphisms could influence SSc susceptibility as well as its clinical or laboratory characteristics in a Chinese Han population. We finally selected eight VDR SNPs (rs731236 (TaqI), rs2228570 (FokI), rs7975232 (ApaI), rs1544410 (BsmI), rs11574010 (Cdx2), rs739837 (BglI), rs757343 (Tru9I) and rs11168267). It is helpful to further understand the mechanism of how VD acts on SSc and to identify of new therapeutic targets.
Section snippets
Patients and Controls
This is a hospital-based case-control study included 100 SSc patients and 100 healthy control subjects. Both SSc and control populations were of Han Chinese. All SSc patients were recruited from the department of Rheumatology at the First Affiliation Hospital of Anhui Medical University and Anhui Provincial Hospital between January 2015 and February 2017. The diagnosis of SSc was performed according to the criteria defined by the 1980 revision of the American College of Rheumatology and
Characteristics of Study Sample
In the current study, for SSc group, mean age and percentage of males was 48.96 ± 12.28 and 8.0%, respectively. Healthy control group included 13 males and 87 females with mean age 50.53 ± 10.45 years. There is no statistically significant difference between these two groups in terms of age (p = 0.331) or sex (p = 0.249). All SSc patients included in this study were diagnosed as diffuse cutaneous SSc. Clinical features of the patients included limitation of mouth opening (65.0%), dyspnea
Discussion
This is a hospital-based case-control study to establish an association between VDR (FokI, TaqI, BsmI, ApaI, Cdx2, BglI, Tru9I and rs11168267) SNPs and SSc susceptibility. In the current study, only ApaI and BglI polymorphism genotype were significantly associated with the risk of SSc. It's worth noting that the frequencies of mutant genotypes were low. The result was inconsistent with the previous study by Kamal A, et al. (16), who demonstrated that no significant differences versus the
Conclusions
In summary, our preliminary study concluded that ApaI and BglI genotype may possibly have a role in the pathogenesis of SSc patients. Additionally, dominant model of ApaI and BglI GT genotype frequency may be associated with the increased risk of ESR.
Acknowledgments
This work were partly supported by grants from the Anhui provincial major project of quality engineering teaching research in 2016 (code:2016jyxm0378), Key Project of the Education Department of Anhui Province Natural Science Research (code: KJ2017A164), Project of visiting study overseas of the excellent youth backbone in the universities of education department of Anhui province in 2017 (code:gxfx2017008), Data Science Center of school of Public Health of Anhui Medical University and Anhui
References (33)
- et al.
Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis
Best Pract Res Clin Rheumatol
(2018) - et al.
Emerging role of vitamin D in autoimmune diseases: an update on evidence and therapeutic implications
Autoimmun Rev
(2019) - et al.
FGF 23, PTH and vitamin D status in end stage renal disease patients affected by VDR FokI and BsmI variants
Clin Biochem
(2018) Vitamin D and cancer: current dilemmas and future research needs
Am J Clin Nutr
(2008)- et al.
Association between VDR polymorphisms and rheumatoid arthritis disease: systematic review and updated meta-analysis of case-control studies
Immunobiology
(2015) - et al.
Effects of vitamin D on the peripheral adaptive immune system: a review
Autoimmun Rev
(2011) - et al.
Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states
J Steroid Biochem Mol Biol
(2004) - et al.
Update on the etiopathogenesis of systemic sclerosis
Rev Bras Reumatol
(2013) - et al.
Vitamin D receptor genetic polymorphism is significantly associated with risk of type 2 diabetes mellitus in Chinese Han population
Arch Med Res
(2015) - et al.
Vitamin D receptor biochemical and genetic profiling and HLA-class II genotyping among Lebanese with multiple sclerosis–A pilot study
J Neuroimmunol
(2016)
Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behçet’s disease in Tunisians
Joint Bone Spine
Pathophysiology of systemic sclerosis: current understanding and new insights
Expert Rev Clin Immunol
Systemic sclerosis
Rev Prat
Association between vitamin D and hypertension in people coming for health check up to a tertiary care centre in South India
J Family Med Prim Care
Vitamin D and skeletal muscle: emerging roles in development, anabolism and repair
Calcif Tissue Int
Vitamin D receptor gene polymorphism: an important predictor of arthritis development
Biomed Res Int
Cited by (14)
Vitamin D attenuates elevated oxidative DNA damage in scleroderma patients with organ involvement: A prospective study
2023, Journal of Steroid Biochemistry and Molecular BiologySerum vitamin D levels and vitamin D receptor gene ApaI and TaqI polymorphisms in patients with morphea: a case–control study
2023, Archives of Dermatological ResearchGenetic Association of VDR gene Apa1 and Taq1 Variants with Sclero-derma in an Iranian Northeast Population
2023, Current Rheumatology Reviews
- ∗
These authors contributed equally to this work.