Vitamin D Levels and Risk of Juvenile Idiopathic Arthritis: A Mendelian Randomization Study

OBJECTIVES: Observational studies report mixed findings regarding the association between vitamin D and JIA incidence or activity, however such studies are susceptible to considerable bias. Since low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation we examined the causal effect of the major circulating form of vitamin D, 25-(OH)D, on JIA incidence using Mendelian randomization (MR).METHODS: In this two sample MR analysis we used summary level data from the largest and most recent genome wide association study (GWAS) of 25-(OH)D levels (sample size 443,734), alongside summary data from two JIA GWASs (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy we employed multiple MR methods and sensitivity analyses.RESULTS: We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (OR 1.00, 95% CI 0.76-1.33 per standard deviation increase in standardised natural-log transformed 25-(OH)D levels). This estimate was consistent across all methods tested. Additonally there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 standard deviation change in standardised natural-log transformed 25-(OH)D levels per doubling odds in genetically predicted JIA, 95% CI -0.006-0.002).CONCLUSION: Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.