Elsevier

Human Immunology

Volume 83, Issue 1, January 2022, Pages 81-85
Human Immunology

Research article
Vitamin D and risk of ankylosing spondylitis: A two-sample mendelian randomization study

https://doi.org/10.1016/j.humimm.2021.09.003Get rights and content

Abstract

Objectives

To study whether Vitamin D levels are causally associated with ankylosing spondylitis (AS).

Methods

Two-sample Mendelian randomization (TSMR) analysis was performed by employing MR-Egger regression, weighted median (WM1), inverse-variance weighted (IVW), and weight mode (WM2) methods. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association.

Results

The results of IVW show that no causal association between vitamin D and AS (OR = 0.999, 95%CI = 0.997, 1.002, P = 0.724). The MR-Egger regression results show that genetic pleiotropy does not bias the results (intercept = −4.474E-05, SE = 2.830E-05, P = 0.255). The MR-Egger method no supported causal association between vitamin D and AS (OR = 1.000, 95%CI = 0.996, 1.005, P = 0.879). WM1 (OR = 1.002, 95%CI = 0.999, 1.005, P = 0.837) and WM2 (OR = 0.998, 95%CI = 0.996, 1.002, P = 0.910) approach also not found a causal relationship between vitamin D levels and AS. The significant heterogeneity was not observed by Cochran's Q test. The “leave-one-out” analysis also proved lack of a single SNP affected the robustness of our results.

Conclusion

Based on our analysis, there is lack of a strong evidence to support a causal inverse association between vitamin D levels and ankylosing spondylitis.

Introduction

Ankylosing spondylitis (AS) is an immune-mediated, chronic, inflammatory disease of the axial spine that can lead to bone hyperplasia and ankylosis [1]. However, until now, the exact cause of AS is still unknown, but it is certain that any single cause cannot fully explain the etiology of AS.

Many environmental and genetic factors are suspected of triggering ankylosing spondylitis, but their role was unclear. Among these, vitamin D supplementation has been identified as a preventive factor, but research on its effect on the development of ankylosing spondylitis has been inconsistent. Vitamin D is a type of lipid-soluble vitamin, but actually contains two related lipid-soluble substances, namely cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). In the liver, vitamin D is metabolized as 25-hydroxyvitamin D [25(OH)D] by microsomal enzymes and hepatocyte mitochondria. The vitamin D3 acts on the intestine, stomach, kidney, and other target organs to regulate calcium and phosphorus levels through its main active metabolites [1,25(OH)D3]. In addition, vitamin D has an immunomodulatory function and is a good selective immunomodulator [2]. When the immune function of the body is inhibited, the immune function can be enhanced by enhancing the functions of monocytes and macrophages [3]. On the contrary, when the immune function is abnormally increased, it will inhibit the proliferation of activated T lymphocyte cells and B lymphocyte cells to maintain the immune balance. Meta-analysis results from previous observational studies indicate that vitamin D levels were inversely associated with the risk of AS [4], [5].

Mendelian randomization (MR) uses genetic variation as instrumental variables (IVs) to determine whether observed correlations between risk factors and outcomes are consistent with causal effects [6]. At present, this approach has been applied to elucidate the causal relationship between the outcomes of disease by exposure factors [7], [8], [9]. Compared with the one-sample MR method, the two-sample MR (TSMR) method is effective and powerful in obtaining associations between “genetic risk factors” and “genetic outcomes” by using the independent results of two genome-wide association studies (GWAS) in the same population [10]. However, this approach has not previously been used to explore the causal relationship between vitamin D and AS risks. In this study, we conducted the TSMR analysis to explore whether vitamin D levels were causally associated with the risk of AS.

Section snippets

Data sources and study design

In our study, single-nucleotide polymorphisms (SNPs) were defined as IVs. To obtain exposure group data, the SNPs closely associated with vitamin D levels (P < 5 × 10−8) at a genome-wide significance level were selected, including 79,366 European-ancestry individuals [11]. To avoid bias due to linkage disequilibrium (LD) relationship in analysis, the LD of SNPs that are closely associated with vitamin D levels has to meet the condition r2 < 0.001 [12]. The SNPs associated with obesity [13],

Instrumental variables

Table 1 describes the characteristic information of SNPs on vitamin D and AS. Finally, we selected four SNPs as IVs (rs3755967, rs12785878, rs10741657 and rs10745742). All of them were associated with vitamin D levels at genome-wide significance. These SNPs explained 5.31% of the variation in vitamin D concentrations. The strength of selected single-IVs, their F-statistics value was ranged from 59 to 1497. Thus, none of these SNPs were excluded for becoming weak IVs.

TSMR analysis results

The results of IVW show that

Discussion

To our knowledge, the causal relationship between vitamin D levels and AS has not been confirmed so far. Therefore, we studied the causal relationship between vitamin D levels and AS. The results of four different estimation methods for the MR analyses were consistent. The TSMR estimate for the serum vitamin D-to-AS relation was unlikely to be causal.

Vitamin D is not only involved in calcium, phosphorus, and bone metabolism, but also has an obvious immunomodulatory effect. It plays an important

Conclusion

In conclusion, the causal effects of vitamin D levels and the risk for AS were not found in our study. Epidemiology suggests that vitamin D levels are inversely associated with AS risk, but this is not the cause-and-effect.

Author contributions

The paper was written through the contributions of all authors. All authors have given approval to the final version of the paper. Jinjin Jiang and Ming Shao contributed equally to this work and should be considered as co-first authors.

Funding

This study was supported by grants from the applied medicine research project of Hefei Health and Family Planning Commission, Anhui Province, China (hwk2016zc019) and the scientific research project of Anhui Blood Center (2015AHBC02).

Conflict of interest

The authors declare that there is no conflict of interest.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

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