Abstract: SA-PO959
SHROOM3 Expression and CKD: A Mendelian Randomization Analysis
Session Information
- CKD: Pathobiology - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Gaheer, Pukhraj Singh, McMaster University Faculty of Arts and Science, Hamilton, Ontario, Canada
- Uppal, Nikhil, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- Bridgewater, Darren, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- Lanktree, Matthew B., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
Background
Genome-wide association studies (GWAS) identified common genetic variants within 100 kilobases of the transcription start site of SHROOM3 individually associated with chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (uACR). This upstream region contains regulatory elements, and the location of these variants suggests that altered SHROOM3 expression could be the mechanism underlying the observed associations. We sought to evaluate if a genetically predicted decrease in SHROOM3 expression was associated with an increased risk of CKD.
Methods
First, we found genetic variants associated with SHROOM3 expression, known as expression quantitative trait loci (eQTL), by conducting a meta-analysis of 7408 genetic variants from 51 tissue datasets from the public Human Kidney eQTL Atlas, GTEx, and NephQTL resources. Independent eQTL variants were then selected to be used in a two-sample Mendelian randomization analysis. Using European ancestry summary-level GWAS results from the CKDGen Consortium, UK Biobank, and the Finnish Genetics Consortium, we compared the effect of each variant on SHROOM3 expression to its effect on risk of CKD (n = 480,698), baseline cross-sectional eGFR (n = 1,201,929), previously defined decline in eGFR phenotypes “Rapid3” or “CKDi25” (n = 141,964), and uACR (n = 547,361).
Results
We identified 50 independent genetic variants associated with SHROOM3 expression (P < 0.05, r2 < 0.01). These variants cumulatively explained 2% of the variability in SHROOM3 expression. A 34% reduction in genetically predicted SHROOM3 expression was associated with a 0.3% (95% CI: 0.1% - 0.5%) reduction in cross-sectional eGFR (P = 0.002). There was no association between genetically predicted SHROOM3 expression and CKD, longitudinal rapid decline in eGFR, or uACR (P > 0.05).
Conclusion
Mendelian randomization analysis suggests a small reduction in genetically predicted SHROOM3 expression throughout life is associated with a slightly lower baseline eGFR. In a seeming contradiction, we did not find that lower genetically predicted SHROOM3 expression was associated with the presence of CKD, rapid decline in eGFR, nor uACR. These results are consistent with recent reports that genetic association with cross-sectional eGFR, maximum attained eGFR, longitudinal decline in eGFR, and risk of CKD may differ.
Funding
- Private Foundation Support