Vitamin D Supplementation in Individuals Heterozygous for SLC34A3 or CYP24A1 Further Increases Nephrolithiasis Risk

Background: Nephrolithiasis affects more than 1 in 10 adults with high heritability. SLC34A3 encodes sodium-dependent phosphate transport protein 2C, and affected individuals are at risk for increased hypercalciuria due to increased calcitriol synthesis. CYP24A1 encodes vitamin D 24-hydroxylase, which catalyzes the catabolism of 25-hydroxyvitamin D. We hypothesized that vitamin D supplementation would be associated with increased risk of nephrolithiasis in individuals heterozygous for SLC34A3 or CYP24A1 pathogenic variants. Methods: Using exome sequencing and electronic health record data from the Geisinger MyCode DiscovEHR study, we identified individuals heterozygous for predicted pathogenic SLC34A3 or CYP24A1 variants, defined by REVEL (score ≥0.7), LOFTEE, or AlphaMissense. Controls had no rare variants [allele frequency <0.01] in the 2 genes. We defined nephrolithiasis using phecode GU_585 and ascertained vitamin D supplementation from medication orders. In logistic regression models, we examined the risk of nephrolithiasis diagnosis by genotype (SLC34A3, CYP24A1, both, or control) and by vitamin D exposure, adjusting for age, sex, race, ethnicity, initial year, and estimated glomerular filtration rate. Interaction terms (genotype x vitamin d) were tested as well. Results: Compared to 142848 controls (9.3%), prevalence of nephrolithiasis was higher among 1152 SLC34A3 heterozygotes (14.8%; OR 1.60, 95% CI: 1.36, 1.88; p<0.001), 2942 CYP24A1 heterozygotes (11.2%; 95% CI: 1.09, 1.37; p=0.001), and 32 dual carriers (18.8%; OR 1.95, 95% CI: 0.80, 4.76; p=0.1). Vitamin D supplementation was associated with increased risk of nephrolithiasis in SLC34A3 heterozygotes (OR 1.69, 95% CI: 1.14, 2.51) and CYP24A1 heterozygotes (OR 1.32, 95% CI: 1.01, 1.74). The effect of vitamin D on increased nephrolithiasis risk tended to be magnified for SLC34A3 (interaction term p value 0.05) but not for CYP24A1 (interaction term p value 0.3). Conclusion: Individuals heterozygous for SLC34A3 and CYP24A1 predicted pathogenic variants are at significantly increased risk of developing nephrolithiasis, and vitamin D supplementation increases risk further. The results of this study could inform a precision medicine approach in mitigating lithogenic risk in those at genetic risk for nephrolithiasis. Funding: Other NIH Support - NIGMS (GM111913)