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Nutrition in acute and chronic diseases

Causal association of genetically determined circulating vitamin D metabolites and calcium with multiple sclerosis in participants of European descent

European Journal of Clinical Nutrition volume 77, pages 481–489 (2023)Cite this article

Subjects

Abstract

Background

Vitamin D is an important regulator of calcium. Mendelian randomization (MR) studies exclusively focused on the circulating total 25-hydroxyvitamin D (25(OH)D) as a biomarker of vitamin D status, and have found the causal association between 25(OH)D and the risk of multiple sclerosis (MS). However, it currently remains unclear about the causal association of the 25(OH)D subtypes including 25(OH)D3 and C3-epi-25(OH)D3, as well as calcium with the risk of MS.

Methods

We performed a two-sample MR study to evaluate the causal association of circulating total 25(OH)D, 25(OH)D3, C3-epi-25(OH)D3, and calcium with the risk of MS using large-scale genome-wide association studies (GWAS) datasets from total 25(OH)D (n = 417,580), 25(OH)D3 (n = 40,562), C3-epi-25(OH)D3 (n = 40,562), calcium (n = 305,349), and MS (14,802 MS and 26,703 controls). We selected five MR methods including inverse-variance weighted (IVW), simple median, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), and contamination mixture method.

Results

IVW showed that the genetically increased circulating 25(OH)D level (OR = 0.81, 95% CI: 0.70–0.94, P = 4.00E-03), circulating 25(OH)D3 level (OR = 0.85, 95% CI: 0.76–0.95, P = 5.00E-03), and circulating C3-epi-25(OH)D3 level (OR = 0.85, 95% CI: 0.74–0.98, P = 2.30E-02) were causally associated with reduced risk of MS. However, IVW showed no causal association between circulating calcium level and the risk of MS with OR = 2.85, 95% CI: 0.42–19.53, P = 2.85E-01.

Conclusions

Our current findings together with evidence from other MR studies support the use of vitamin D but not calcium supplementation for the prevention of MS.

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Fig. 1: The flow chart about the MR study design.
Fig. 2: Individual estimates about the causal effect of circulating 25(OH)D on MS using IVW method.
Fig. 3: Individual estimates about the causal effect of circulating 25(OH)D3 on MS using IVW method.

Data availability

All data generated or analyzed during this study are included in this published article and its Additional files. The authors confirm that all data underlying the findings are either fully available without restriction through consortia websites, or may be made available from consortia upon request. International Multiple Sclerosis Genetics Consortium (IMSGC): https://imsgc.net/.

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Acknowledgements

We thank International Multiple Sclerosis Genetics Consortium (IMSGC) for the GWAS summary statistics.

Funding

This work was supported by funding from the National Natural Science Foundation of China (Grant No. 82071212, and 81901181), Beijing Natural Science Foundation (Grant No. JQ21022), the Mathematical Tianyuan Fund of the National Natural Science Foundation of China (Grant No. 12026414), and Beijing Ten Thousand Talents Project (Grant No. 2020A15). This work was also partially supported by funding from the Science and Technology Beijing One Hundred Leading Talent Training Project (Z141107001514006), the Beijing Municipal Administration of Hospitals’ Mission Plan (SML20150802), the Funds of Academic Promotion Programme of Shandong First Medical University & Shandong Academy of Medical Sciences (No. 2019QL016, No. 2019PT007).

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Authors and Affiliations

  1. Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China

    Yan Zhang

  2. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Haijie Liu

  3. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China

    Haihua Zhang & Guiyou Liu

  4. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China

    Zhifa Han

  5. Chinese Institute for Brain Research, Beijing, China

    Tao Wang & Guiyou Liu

  6. Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China

    Longcai Wang

  7. Key Laboratory of Cerebral Microcirculation in Universities of Shandong; Department of Neurology, Second Affiliated Hospital; Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China

    Guiyou Liu

  8. Beijing Key Laboratory of Hypoxia Translational Medicine, National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Guiyou Liu

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Contributions

GYL and YZ conceived and initiated the project. GYL and YZ analyzed the data, and wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.

Corresponding author

Correspondence to Guiyou Liu.

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The authors declare no competing interests.

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This article contains human participants collected by several GWAS. All participants gave informed consent in all the corresponding original studies. Here, we only used the large-scale GWAS summary datasets, and not the individual-level data. Hence, ethical approval was not sought.

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Zhang, Y., Liu, H., Zhang, H. et al. Causal association of genetically determined circulating vitamin D metabolites and calcium with multiple sclerosis in participants of European descent. Eur J Clin Nutr 77, 481–489 (2023). https://doi.org/10.1038/s41430-023-01260-4

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