Abstract: TH-OR018
Experimentally Validated SLC6A19 Loss-of-Function Variants Improve Kidney Function and Reduce Progression to Kidney Failure
Session Information
- CKD: Exploring Intertwined Mechanisms of Disease Progression
November 06, 2025 | Location: Room 362A, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: CKD (Non-Dialysis)
- 2301 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention
Authors
- Mozaffari, Sahar V., Maze Therapeutics Inc, South San Francisco, California, United States
- De Jong, Hannah N, Maze Therapeutics Inc, South San Francisco, California, United States
- Scherer, Nora, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
- Butz, Elena, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
- Ullman, Julie, Maze Therapeutics Inc, South San Francisco, California, United States
- Sallee, Nathan A, Maze Therapeutics Inc, South San Francisco, California, United States
- Hoek, Maarten, Maze Therapeutics Inc, South San Francisco, California, United States
- Graham, Robert R., Maze Therapeutics Inc, South San Francisco, California, United States
- Kottgen, Anna, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
- Estrada, Karol, Maze Therapeutics Inc, South San Francisco, California, United States
Background
Chronic kidney disease (CKD) is associated with reduced kidney function and may progress to kidney failure. Loss of Function (LOF) variants in SLC6A19 have one of the strongest associations in the genome with improved kidney function (UK biobank: eGFR beta = 0.15, p = 5.35e-36). The missense variant D173N is associated with higher eGFR (beta = 0.14, p = 9.38e-23) and protection from CKD (OR: 0.87, p = 2.64e-3).
Methods
We compiled SLC6A19 variants (allele count >1) from UK Biobank (UKB), All of Us (AOU), and German CKD (GCKD) cohorts for experimental variant functionalization. We aim to identify experimental loss-of-function (xLOF) variants expected to have kidney-protective effects undetected in population genetic studies. We performed burden and survival analyses with xLOF variants to elucidate the role of SLC6A19 on eGFR and CKD progression. CKD progression was modeled by time to a composite kidney endpoint (CKE; 40% eGFR decline, eGFR <15 mL/min/1.73m2, dialysis, or transplant).
Results
Of the variants tested experimentally, 200 had low protein abundance compared to WT (p<0.05) that we defined as xLOF variants. The xLOF variants present in UKB (n=176) are significantly associated with higher eGFR (beta = 0.129, p = 1.21e-13). Identification of these xLOF variants doubled our LOF carriers. Combining xLOF variants, D173N, and existing pLOFs, we find more significant associations with higher eGFR (beta = 0.15, p = 5.57e-38), replicated in AOU (beta = 0.070, p = 1.94e-03).
With the xLOF variants, D173N, and existing pLOF variants we see significantly decreased risk of CKE over time in UK Biobank (HR: 0.648, p=0.0251). Additionally, we found decreased risk of CKE in CKD cases in meta-analyses of GCKD (stage 3 CKD) and UKB (stage 2 CKD) (HR = 0.51, p = 0.001).
Conclusion
Variant functionalization assays yielded insight into the impact of rare genetic variants beyond genetic studies. Variants classified as xLOF in our assay correspond to higher eGFR. We show for the first time SLC6A19 loss of function variants are associated with lower risk of CKE both broadly and in those with CKD. These results inform our mechanistic understanding of SLC6A19 genetics and support the therapeutic potential for inhibition of SLC6A19 as a treatment in CKD population.
Funding
- Commercial Support – Maze Therapeutics