Abstract: FR-PO640
Individuals Heterozygous for SLC34A3 Predicted Pathogenic Variants Are at Increased Risk of Nephrolithiasis
Session Information
- Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Chang, Alexander R., Geisinger Health, Danville, Pennsylvania, United States
- Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States
- Luo, Jonathan Z., Geisinger Health, Danville, Pennsylvania, United States
- Bucaloiu, Ion D., Geisinger Health, Danville, Pennsylvania, United States
- Cogal, Andrea G., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- McDonnell, Shannon K., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Frank, Jacob A., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Scheinman, Steven J., Geisinger Health, Danville, Pennsylvania, United States
- Ma, Jun, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Lieske, John C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Prior studies have suggested that individuals heterozygous for SLC34A3 pathogenic variants are at risk for nephrolithiasis, but this association has not been examined comprehensively.
Methods
We used data from Geisinger MyCode/DiscovEHR (n=174,172) and the Mayo Clinic Biobank (MCBB) (n=43,743), health system-based cohorts with exome sequencing and electronic health records. An electronic phenotyping algorithm for nephrolithiasis was developed and validated in the 2 cohorts. Gene burden tests were completed using several masks based on pathogenicity predictions from LOFTEE, REVEL, and AlphaMissense (AM). We considered a Bonferroni-corrected p value <0.00714 significant. Variant-specific analyses were done using Firth logistic regression models. Analyses were adjusted for age, sex, and genetic ancestry.
Results
Prevalence of predicted pathogenic SLC34A3 variants ranged from 0.00095 (LOFTEE) to 0.0037 (LOFTEE or AM or REVEL). Predicted pathogenic variants in SLC34A3 using 4 of the 7 masks were associated with nephrolithiasis in MyCode (Table). Replication analyses in MCBB showed a modest association signal. In MyCode, several variants were associated with nephrolithiasis [Ser192Leu (OR 1.73; p=0.005) and Ser138Phe (OR 2.06; p=0.006)], or of borderline significance [Met403Arg (OR 2.36; p=0.1), Thr202Ile (OR 2.43; p=0.1), Met145Ile (OR 3.78; p=0.1), Gly518Arg (OR 4.13; p=0.05)]. Ser138Leu was the strongest association seen in MCBB (OR 4.65; p=0.001).
Conclusion
One in 270 individuals were carriers of SLC34A3 predicted pathogenic variants, which were associated with increased risk of nephrolithiasis. Future studies are needed to understand the impact of SLC34A3 on kidney stone severity, recurrence risk, and whether personalized treatment of these individuals can reduce nephrolithiasis burden.
Gene Burden test for SLC34A3 and nephrolithiasis
| Geisinger ACATO p-value | Mayo ACATO p-value | |
| LOFTEE | 0.061 | 0.016 |
| REVEL | 0.040 | 0.073 |
| Alpha Missense (AM) | 1.31E-07 | 0.060 |
| REVEL or AM | 2.51E-07 | 0.045 |
| LOFTEE or AM | 3.29E-08 | 0.027 |
| LOFTEE or REVEL | 0.013 | 0.004 |
| LOFTEE or AM or REVEL | 6.03E-08 | 0.012 |
Funding
- NIDDK Support