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Vitamin D and human health: evidence from Mendelian randomization studies

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Abstract

We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.

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Data availability

The data reported in this manuscript have been previously published. Data collection form, data extracted from included studies, and data used for all analyses are available in the supplementary material.

Abbreviations

25(OH)D:

25-Hydroxyvitamin D

1,25(OH)2D:

1,25-Dihydroxyvitamin D

ALS:

Amyotrophic lateral sclerosis

BCC:

Basal cell carcinoma

CAD:

Coronary artery disease

CHD:

Coronary heart disease

CI:

Confidence interval

CVD:

Cardiovascular disease

FIND:

Finnish vitamin D trial

GI:

Genetic instrument

GWAS:

Genome-wide association study

HF:

Heart failure

HR:

Hazard ratio

IV:

Instrumental variable

KSD:

Kidney stone disease

MI:

Myocardial infarction

MR:

Mendelian randomization

MS:

Multiple sclerosis

NAFLD:

Nonalcoholic fatty liver disease

OR:

Odds ratio

RCT:

Randomized controlled trial

SD:

Standard deviation

SE:

Standard error

SNP:

Single nucleotide polymorphisms

T2D:

Type 2 diabetes

UKB:

UK biobank

VDR:

Vitamin D receptor

ViDA:

Vitamin D assessment study

VITAL:

Vitamin D and omega-3 trial

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Acknowledgements

The authors thank Yunshan Li, Xiaocong Dong, Mingjie Zhang, and Jing Shu from the School of Public Health, Sun Yat-sen University for their assistance in checking the extracted data and presenting the results.

Funding

This work was supported by the National Natural Science Foundation of China (81803219) and the Natural Science Foundation of Guangdong Province, China (2018A030310335). The sponsors had no role in the study design, data analysis or interpretation of results.

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Authors and Affiliations

  1. Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China

    Aiping Fang & Yue Zhao

  2. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA

    Aiping Fang, Xuehong Zhang & Edward L. Giovannucci

  3. School of Nursing, Peking University, Beijing, China

    Ping Yang

  4. School of Nursing, Johns Hopkins University, Baltimore, MD, USA

    Ping Yang

  5. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Xuehong Zhang

  6. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Edward L. Giovannucci

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Contributions

ELG and AF conceptualized the review; AF designed the search strategy and performed the literature search; AF and YZ screened abstracts and full-texts; AF and YZ extracted the data; AF, YZ and PY checked the data; YZ, PY and AF assessed the methodological quality of the included studies; AF and YZ analyzed the data; AF wrote the original draft of the manuscript; ELG and XZ edited and critically reviewed the original draft of the manuscript; ELG had primary responsibility for the final content; and all authors read and approved the final manuscript.

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Correspondence to Edward L. Giovannucci.

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Fang, A., Zhao, Y., Yang, P. et al. Vitamin D and human health: evidence from Mendelian randomization studies. Eur J Epidemiol (2024). https://doi.org/10.1007/s10654-023-01075-4

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