Kidney Week

Abstract: FR-PO639

UMOD p.Thr62Pro Pathogenicity Is Modified by Polygenic CKD Risk

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

Alexander R. Chang, MD, MS

• Dinsmore, Ian, Geisinger Health, Danville, Pennsylvania, United States

Ian Dinsmore, MS

• Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States

Bryn S. Moore, MS

• Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States

Anthony J. Bleyer, MD, MS, FASN

• Mirshahi, Tooraj, Geisinger Health, Danville, Pennsylvania, United States

Tooraj Mirshahi, PhD

Background

UMOD p.Thr62Pro has been reported as having intermediate penetrance for chronic kidney disease (CKD) with end-stage kidney disease (ESKD) occurring at a median of ~70 years of age. Since p.Thr62Pro results in an intermediate intracellular trafficking defect, we hypothesized that age and CKD polygenic risk would modify the association of Thr62Pro with estimated glomerular filtration rate (eGFR).

Methods

Using data from Geisinger MyCode/DiscovEHR, a health system-based cohort with exome sequencing and electronic health record data, we created a polygenic risk score (PRS) using summary statistics from the UK Biobank for individuals of European ancestry. Heterozygotes with UMOD p.Thr62Pro were compared to those without UMOD rare variants using linear regression for continuous outcomes and Firth logistic regression for categorical outcomes, adjusted for age, sex, and race. Primary outcome was most recent eGFR. Secondary outcomes included eGFR<60, eGFR <30, gout, and ESKD. We tested for an interaction by age ≥ or < 60 years, and conducted subgroup analyses by age group.

Results

UMOD p.Thr62Pro heterozygotes (median age 61, interquartile interval 46-72) had increased risk of ESKD (OR 2.91, 95% CI: 1.23, 6.91; p=0.02), eGFR <30 (OR 2.21, 95% CI: 1.15, 4.25; p=0.02), eGFR <60 (OR 1.64, 95% CI: 1.02, 2.64), but not gout (OR 0.48, 95% CI: 0.14, 1.71). The association of UMOD p.Thr62Pro with eGFR was stronger in adults ≥60 vs. <60 years of age (p=0.04 for interaction term) with lower eGFR for heterozygotes ≥60 years of age (-7.29 ml/min/1.73m², 95% CI: -2.60, -1.98) and a smaller effect for those <60 years of age (3.79, 95% CI: -1.21, 8.79; p=0.1). CKD PRS was associated with lower eGFR in UMOD p.Thr62Pro (per SD: -7.28 ml/min/1.73m2, 95% CI: -11.40, -3.16).

Conclusion

Adults with the intermediate-penetrance UMOD p.Thr62Pro variant experience increased risk of eGFR decline after 60 years of age, and risk is modified by CKD PRS.

Funding

• NIDDK Support