Serum vitamin D levels and Sjogren’s syndrome: bi-directional Mendelian randomization analysis

(2023) 25:79 Zhao et al. Arthritis Research & Therapy https://doi.org/10.1186/s13075-023-03062-2 Arthritis Research & Therapy Open Access RESEARCH Serum vitamin D levels and Sjogren’s syndrome: bi‑directional Mendelian randomization analysis Meng Zhao1†, Feiran Wei2†, Han Li1, Zemin Wang1, Shuai Wang1, Yangyang Liu1, Gaoqiang Fei1, You Ge1 and Pingmin Wei1* Abstract Background Based on the results of existing observational studies, it can be found that the association between serum vitamin D levels and the risk of Sjogren’s syndrome (SS) in humans is still controversial. Based on this situation, this study aimed to assess the causal relationship between serum vitamin D levels and SS by using the Mendelian randomization (MR) approach. Methods In this study, genome-wide association studies (GWAS) summary statistics on serum vitamin D levels [sample size = 417,580 (UK Biobank)] and SS [sample size = 416,757 (cases = 2495, controls = 414,262) (FinnGen)] were used. The bi-directional MR analysis was then used to assess possible causal relationships. The major analysis method of MR was performed using inverse-variance weighted (IVW), supplemented by MR-Egger and the weighted median approaches. In addition, sensitivity analyses were used to ensure the stability of the results, including Cochran’s Q test, MR-PRESSO, MR-Egger intercept test, and the leave-one-out test. Results The MR suggested that no significant causal effects of serum 25(OH)D levels on SS risks were observed [odds ratio (OR) = 0.9824; 95% confidence interval (CI) = 0.7130 to 1.3538; P = 0.9137]. Similarly, no evidence supported the causal effects of SS on serum vitamin D levels (β: 0.0076, 95% CI: − 0.0031 to 0.0183; P = 0.1640). Conclusion This study found no obvious evidence that serum vitamin D level is causally associated with SS risks or vice versa. We call for larger sample size studies to further unravel the potential causal relationship and the exact mechanism. Keywords Mendelian randomization, Vitamin D, 25(OH)D, Sjogren’s syndrome Meng Zhao, Feiran Wei these authors contributed equally to this work and share the first authorship. *Correspondence: Pingmin Wei 1 Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing 210009, Jiangsu, China 2 Division of Rheumatology, Zhongda Hospital Southeast University, Nanjing 210008, Jiangsu, China Introduction Sjogren’s syndrome (SS) is a complex, heterogeneous systemic chronic autoimmune disorder commonly presenting with dry eyes and mouth [1–3]. SS is one of the most common autoimmune diseases with a prevalence of 0.1 to 4.8% in various populations, according to the strict definition of the American-European Consensus Criteria [4–6]. SS can cause damage to almost any organ or system causing a variety of complications, including immune thrombocytopenia, interstitial lung disease, autoimmune hepatitis, and lymphoma to name © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhao et al. Arthritis Research & Therapy (2023) 25:79 just a few [7], which places a tremendous financial burden on patients’ families and healthcare services [8]. In addition, SS can cause fatigue, depression, anxiety, and decreased physical performance, which in turn seriously affects the patient’s quality of life [5]. Vitamin D is a nutrient with multiple biological effects and its main form in serum is 25-hydroxyvitamin D [25(OH)D], which plays an important role in immune regulation [9, 10]. Currently, low levels of vitamin D due to lack of sunlight exposure or low dietary intake have been identified as a major risk factor for autoimmune diseases [11]. There have been several observational studies exploring the association between vitamin D and SS risk. Recently, two large cross-sectional studies including 107 and 176 SS patients from Turkey [12] and Europe [13] were conducted. The former study found no difference in vitamin D levels between cases and controls, while the latter reported lower levels of vitamin D levels in patients with SS. In addition, a cohort study demonstrated that vitamin D deficiency is common in SS patients [12], and a meta-analysis based on the observational studies also obtained the same results [14]. Based on the above, there are inconsistent results regarding the association between vitamin D levels and SS. Conclusions about causality cannot be drawn solely from the results in observational designs, possibly because of the limitations contained in the cohort and cross-sectional studies (limited sample size, different races, and other existing confounding factors and bias). Currently, it is uncertain whether the relationship between vitamin D and SS is causal, and whether it operates in one or both directions. Mendelian randomization (MR) analysis is a useful epidemiological research strategy for assessing causal relationships. With the development and advancement of the Human Genome Project, MR analysis uses genetic variants as instrumental variables (IVs), which minimizes the limitations of observational studies and yields unconfounded information on the causal relationship between exposure and outcome through its specific analytical methods [15, 16]. IVs typically use single nucleotide polymorphisms (SNPs) obtained from genome-wide association studies (GWAS), which are DNA sequence polymorphisms induced by single nucleotide mutation within the genome [17]. According to the principle of independent classification (Mendel’s law of random allocation), genetic variants are randomly assigned during meiosis [18]; thus, they can be considered hereditary randomized controlled trials (RCTs) and may not be affected by residual confounding and reverse causality. Based on this, the study was to examine the causal association between serum vitamin D and SS, using the data from large-scale GWAS with the bi-directional MR design. Page 2 of 9 Materials and methods Ethics This study was reported acco (...truncated)