No evidence of a causal relationship has been shown between genetically predicted levels of the major circulating form of vitamin D — 25-(OH)D — and juvenile idiopathic arthritis (JIA), according to study results published in Arthritis Care & Research (Hoboken).

A first-of-its-kind Mendelian randomization (MR) study was conducted to explore the potential causal effect of vitamin D on risk for JIA.

Recognizing that observational data regarding the link between vitamin D levels and JIA has showed mixed results, the researchers sought to limit any bias due to confounding and reverse causation by using MR in their analysis. They conducted a 2-sample MR analysis in which they used summary-level data from the largest, most recent genome-wide association study (GWAS) of 25-(OH)D levels (sample size of 443,734), along with summary data from 2 JIA GWASs (sample sizes of 15,872 and 12,501). Samples were from collected from European populations.

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A total of 69 vitamin D-associated single-nucleotide polymorphisms (SNPs) were used as instruments with sufficient strength for MR analysis. Researchers observed no evidence that higher genetically predicted 25-(OH)D levels were causally linked to a reduced risk for JIA (odds ratio [OR], 1.00; 95% CI, 0.76-1.33).

In a “leave-one-out” analysis that was also conducted, no single SNP was shown to drive the MR estimates. According to the JIA sample size of 12,501, the current study has 80% power to detect effects as small as an OR of 1.47 per SD change in standardized natural-log transformed 25-(OH)D levels and 100% power to detect an OR of 1.80 per SD change in standardized natural-log transformed 25-(OH)D levels.

Further, no evidence was presented to show that genetically predicted JIA causally affects 25-(OH)D levels (-0.002 SD change in standardized natural-log transformed 25-(OH)D levels per doubling odds in genetically predicted JIA; 95% CI, -0.006 to 0.002).

The researchers concluded that based on the lack of a causal association between 25-(OH)D levels and JIA, population-level supplementation with vitamin D was not likely to decrease the incidence of JIA.

They concluded, “Further interrogation of these findings with larger, ethnically diverse and subtype specific datasets would be beneficial. In addition, the role of vitamin D in JIA disease activity and thus the utility of vitamin D supplementation as a treatment adjunct, warrants further investigation.”

Disclosure: One of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 


Clarke SLN, Mitchell RE, Sharp GC, Ramanan AV, Relton CL. Vitamin D levels and risk of juvenile idiopathic arthritis: A Mendelian randomization study. Arthritis Care Res (Hoboken). Published online November 8, 2021. doi:10.1002/acr.24815