Abstract: FR-PO636
Genome-Wide Association Study of GFR Slope Decline in a Diverse Cohort from the Million Veteran Program
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
- Hung, Adriana, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Triozzi, Jefferson Lorenzo, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Chen, Hua-Chang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yu, Zhihong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wilson, Otis D., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wang, Guanchao, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Ikizler, Talat Alp, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Hsi, Ryan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Wheless, Lee, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Siew, Edward D., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Group or Team Name
- Million Veteran Program.
Background
Rapid chronic kidney disease (CKD) progression is associated with poor outcomes and interventions to slow progression are scarce. Only a few genetic loci have been associated with kidney function decline, as assessed by eGFR slope over time. We here perform the largest and most diverse investigation of genetic determinants of eGFR slope to date.
Methods
We performed a genome-wide association study (GWAS) of eGFR decline among 541,845 individuals enrolled in the Million Veteran Program. Our primary outcome was the annualized relative slope defined as longitudinal change in outpatient eGFR (% change per year), adjusted for age, sex, and 10 principal components of ancestry. Analyses were stratified by genetic ancestry and diabetes and inverse variance-weighted fixed-effect meta-analyses were carried out using and METAL.
Results
The strongest trans-ancestry association in patients with diabetes was in PDILT/UMOD (rs77924615; p=3x10-42). Other significant associations in patients with diabetes included SLC47A1 (rs2247436 p = 1x10-15), BICC1 (rs10763564 p=3x10-9), NDST4 (rs144322816 p=5x10-8). In non-diabetic individuals, associations were noted at PDILT (rs77924615; p= 1x10-45), BICC1 (rs1649081; p=2x10-10), AZIN2 (rs116832156; p=6x10-10), TRIM62 (rs116120304; 1x10-9), PRKGA2 (rs10265221; p=2x10-9), WDR72 (rs689751; p=2x10-9); TPPP (rs4990988; 1x10-8), RORA-AS1 (rs919582144; p=4x10-8). In the overall meta-analysis, associations included SLC47A1 (rs2440155; p=3x10-11), PDILT/UMOD (rs77924615; p=3x10-82), WDR72 (rs6416452;p=1x10-13), BICC1 (rs34275789; p=3x10-17), PRKGA2 (rs10265221; p=1x10-13), RORA-AS1 (rs919582144; p=4x10-8), APOE (rs429358, p=3x10-8), PLCH1 (rs3851357; p=1x10-8), GP2 (rs62032857;7x10-9) and several intergenic loci with GWAS significance near LINC02694, PRDM8, OR52E1, NIRP.
Conclusion
Sixteen loci (three novel) were associated with longitudinal changes with GWAS significance and multiple with nominal association. SLC47A1, BICC1 and APOE are being study as potential targets. Meta-analysis with 125,000 participants in BioVU is underway. This work will provide the basis for the construction of a diverse CKD polygenic risk score and will allow for exploration of druggable targets using actionable proteins.
Funding
- Veterans Affairs Support