Abstract: TH-OR036
Vitamin D Supplementation in Individuals Heterozygous for SLC34A3 or CYP24A1 Further Increases Nephrolithiasis Risk
Session Information
- Genetics of Complex Kidney Traits
November 06, 2025 | Location: Room 360A, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits
Authors
- Xu, Kevin, Geisinger, Danville, Pennsylvania, United States
- Bucaloiu, Andrei, Geisinger, Danville, Pennsylvania, United States
- Moore, Bryn S., Geisinger, Danville, Pennsylvania, United States
- Mirshahi, Tooraj, Geisinger, Danville, Pennsylvania, United States
- Scheinman, Steven J., Geisinger, Danville, Pennsylvania, United States
- Bucaloiu, Ion D., Geisinger, Danville, Pennsylvania, United States
- Chang, Alexander R., Geisinger, Danville, Pennsylvania, United States
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