Kidney Week

Abstract: TH-OR063

Polygenic Risk Score for Circulating 1,25-Hydroxyvitamin D and Application to Risk of Kidney Stones

Session Information

• New Developments in Bones, Stones, and Mineral Metabolism
  November 06, 2025 | Location: Room 370A, Convention Center
  Abstract Time: 05:50 PM - 06:00 PM

Category: Bone and Mineral Metabolism

• 502 Bone and Mineral Metabolism: Clinical

Authors

• Ferraro, Pietro Manuel, Universita degli Studi di Verona, Verona, Veneto, Italy

Pietro Manuel Ferraro, MD, MS, PhD

• Curhan, Gary C., Brigham and Women's Hospital, Boston, Massachusetts, United States

Gary C. Curhan, MD, ScD, FASN

Background

Polygenic risk scores (PRS) summarize the effects of multiple common genetic variants on a given trait or condition. No previous studies have created a PRS for circulating 1,25-dihydroxy vitamin D (1,25-D) or validated its clinical association with incident kidney stones (KS).

Methods

We included 2370 women in the Nurses’ Health Study (NHS) and 425 men in the Health Professionals Follow-up Study with available measured 1,25-D and genotyping data (imputation using HRC). SNPs with minor allele frequency>0.01 and imputation r² >0.3 were considered. To derive a PRS for 1,25-D, we used the lasso sum penalized regression framework among 936 NHS participants with genotyping data from the Illumina OmniExpress platform. The PRS was tested in the remaining NHS and HPFS participants; Pearson r's >0.71 between predicted and measured 1,25-D levels. The weights associated with each SNP (p<0.0005) were used to calculate the PRS for 1,25-D in the full HPFS (n=10,938) and NHS (n=11,605) cohorts with genetic data. KS was self-reported and confirmed through biennial questionnaires. Individuals with previous KS at baseline were excluded. Kaplan-Meier (KM) curves were used to examine the association between quintiles of PRS and incident KS, starting at study inclusion and ending when either KS, death, cancer or censoring occurred.

Results

There were 874 incident KS in HPFS (1986-2012) and 635 in NHS (1990-2020). KM curve for quintiles of PRS and incident KS for NHS is shown in Figure. In both cohorts, those in the highest quintiles of PRS showed highest risk of KS formation.

Conclusion

A PRS for circulating 1,25-D shows a dose-response relation with incident KS formation. This approach allows exploration of the association between 1,25-D and clinical outcomes, even in the absence of information on circulating 1,25-D values.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025szvea1ps