Genetically Predicted Lifelong Circulating 25(OH)D Levels are Associated With Serum Calcium Levels and Kidney Stone Risk

Objective: To assess whether lifelong higher circulating 25-hydroxyvitamin D [25(OH)D] levels increase serum calcium levels and kidney stone disease (KSD) risk.

Methods: Summary data for KSD were obtained from the UK biobank genome-wide association study (6536 cases and 388 508 controls). We acquired summary data for 25(OH)D from 120 618 Europeans and another large-scale analysis (443 734 Europeans) for primary and secondary analysis. Random-effect inverse-variance weighted (IVW) and 7 additional sensitivity analyses were applied. Next, multivariable Mendelian randomization (MVMR) was performed by introducing data for serum calcium levels.

Results: Genetic predisposition for a 1-SD higher 25(OH)D level was associated with increased serum calcium levels (IVW; beta, 0.014; 95% CI, 0.010-0.018; P = 7.64E-10). Genetically predicted higher circulating 25(OH)D levels were associated with increased the risk of KSD, with per 1-SD odds ratios (ORs) of 1.47 (95% CI, 1.22-1.77; P = 5.49E-05) and 1.36 (95% CI, 1.03-1.80; P = 0.029) using the IVW and MVMR-Egger methods, respectively. In secondary analysis, similar results were found: 25(OH)D was associated with an increased risk of KSD in univariate Mendelian randomization (IVW; OR 1.71; 95% CI, 1.26-2.32; P = 0.001) and MVMR (OR 1.43; 95% CI, 1.16-1.76; P < 0.001) analyses. Most sensitivity analyses were consistent with the primary results, both for the primary and secondary analyses.

Conclusions: Our study supports that higher genetically predicted lifelong circulating 25(OH)D levels are associated with higher calcium levels and KSD risk. The effects of 25(OH)D on KSD were partially attenuated-but still significant-in MVMR.