Preliminary Report
Associations of Vitamin D Receptor Single Nucleotide Polymorphisms with Susceptibility to Systemic Sclerosis

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Background

This study aims to evaluate whether the Vitamin D receptor (VDR) gene polymorphisms were associated with systemic sclerosis (SSc) in a Chinese Han population.

Methods

Using a hospital-based case-control study including 100 SSc patients and 100 healthy controls. Single nucleotide polymorphisms (SNPs) in the VDR region were genotyped by the improved multiplex ligase detection reaction (i MLDR) method. Haplotypes were also constructed after linkage disequilibrium (LD) analysis.

Results

Eight SNPs (rs731236 (TaqI), rs2228570 (FokI), rs7975232 (ApaI), rs1544410 (BsmI), rs11574010 (Cdx2), rs739837 (BglI), rs757343 (Tru9I) and rs11168267) were included. There were significant differences between SSc patients and healthy individuals in ApaI and BglI genotype (both adjusted p = 0.008). Through the genotyping, significantly association of SSc were found for: dominant model of ApaI and BglI (both OR (95% CI) = 1.80 (1.03,3.16), p = 0.040). Furthermore, the elevation of erythrocyte sedimentation rate (ESR) had a higher percentage of BglI GT genotype frequency (p = 0.034) and dominant model of ApaI (p = 0.016) in SSc. There was high linkage disequilibrium was detected in BglI and ApaI polymorphisms (r2 = 1.0, D’ = 1.0), Tru9I and rs11168267 (r2 = 0.926, D’ = 0.969), respectively. No significant difference were found in these four haplotypes (all p >0.05). The correlation between VD levels and VDR gene polymorphisms was not statistically significant.

Conclusions

Our preliminary study indicates the ApaI and BglI genotype may possibly have a role in the pathogenesis of SSc patients. Dominant model of ApaI and BglI GT genotype frequency may be associated with the increased risk of ESR.

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

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    These authors contributed equally to this work.

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