Assessment of causal associations between uric acid and 25-hydroxyvitamin D levels

BackgroundPrevious observational studies have revealed the association between serum uric acid and 25-hydroxyvitamin D. However, the causality and the direction of the associations remain unknown. Thus, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis to investigate the causal association between uric acid and 25-hydroxyvitamin D and to determine the direction of the association. MethodBased on the summary-level GWAS data from large genome-wide association studies, several steps were taken in our analysis to select eligible single-nucleotide polymorphisms (SNPs), which were strongly related to exposure as the instrumental variables. We used different analytical methods, such as inverse-variance weighting (IVW) method, weighted median, MR-Egger regression, and weighted mode method, to make our result more robust and reliable. The IVW method was used as the primary analysis. The Cochran's Q test, MR-Egger intercept test, MR-PRESSO method, and leave-one-out sensitivity analysis was performed to evaluate the heterogeneities, horizontal pleiotropy, and robustness of the results. MR analyses were also conducted using genetic risk scores (GRS) as instrumental variables in both directions by using the same summary-level GWAS data. ResultsOur two-sample MR analysis suggested a causal association of genetically predicted uric acid on 25-hydroxyvitamin D [IVW method: beta(SE), -0.0352(0.0149); p = 0.0178], which suggested that a per mg/dl increase in uric acid was associated with a decrease of 0.74 nmol/L of 25-hydroxyvitamin D, and the above results remained stable in the sensitivity analysis. By contrast, four MR methods suggested no causal relationship of 25-hydroxyvitamin D on serum uric acid [IVW beta(SE), 0.0139 (0.0635); p = 0.826; MR-Egger beta(SE), 0.0671 (0.108); p = 0.537; weighted median beta(SE), 0.0933 (0.0495); p = 0.0598; weighted mode beta(SE), 0.0562 (0.0463); p = 0.228, respectively]. After excluding the SNPs, which were associated with confounding factors and outlier SNPs, the IVW method suggested that there was still no causal association of 25-hydroxyvitamin D on serum uric acid. The GRS approach showed similar results. ConclusionsSerum uric acid may causally affect the 25-hydroxyvitamin D levels, whereas the causal role of 25-hydroxyvitamin D on uric acid was not supported in our MR analysis. Our findings suggest that increased levels of uric acid should prompt investigation for vitamin D deficiency.

Automated summary

This study used a two-sample bidirectional Mendelian Randomization analysis to investigate the causal association between serum uric acid and 25-hydroxyvitamin D and to determine the direction of the association. The results suggested a causal association of genetically predicted uric acid on 25-hydroxyvitamin D, while no causal relationship was found for 25-hydroxyvitamin D on serum uric acid.