Kidney Week

Abstract: TH-PO742

Multi-Ancestry Proteo-Genomic Association Study of eGFR

Session Information

• Diversity and Equity in Kidney Health - I
  November 03, 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

• Lanktree, Matthew B., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Matthew B. Lanktree,

• Perrot, Nicolas, Population Health Research Institute, Hamilton, Ontario, Canada

Nicolas Perrot,

• Smyth, Andrew, Population Health Research Institute, Hamilton, Ontario, Canada

Andrew Smyth,

• Narula, Sukrit, Population Health Research Institute, Hamilton, Ontario, Canada

Sukrit Narula,

• Pigeyre, Marie, Population Health Research Institute, Hamilton, Ontario, Canada

Marie Pigeyre,

• Krepinsky, Joan C., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Joan C. Krepinsky,

• Yusuf, Salim, Population Health Research Institute, Hamilton, Ontario, Canada

Salim Yusuf,

• Pare, Guillaume, Population Health Research Institute, Hamilton, Ontario, Canada

Guillaume Pare,

Background

Reduced eGFR impacts the concentration of proteins circulating in the plasma. Biomarkers may be released during injury without being harmful themselves. Thus, biomarker studies of CKD are prone to confounding by reverse causation. The concentration of plasma protein biomarkers is also influenced by genetic variation. As genotypes are static from birth, life-long differences in genetically predicted protein concentration can be used to identify potentially causal pathogenic or protective proteins while minimizing confounding and reverse causality. Jointly considering the impact of multiple variants on life-long protein concentration can discover novel associations in addition to variants identified in genome-wide association studies (GWAS). In a proteo-genomic association study, we sought to test the impact of genetically predicted variation in 1,161 plasma proteins on eGFR.

Methods

We searched for cis protein quantitative trait loci (pQTL) genetic variants associated with the concentration of 1,161 plasma proteins in a multi-ancestry sample of 10,753 participants from the Prospective Urban and Rural Epidemiological (PURE) study. Using two-sample Mendelian randomization, we tested if pQTL variants were also associated with eGFR and kidney traits in >1 million participants of published GWAS. We also examined colocalization of pQTL signals and eGFR GWAS results and the phenome-wide impact of genetically altered concentration of the identified proteins.

Results

419 pQTL instruments were constructed in PURE including 4665 genetic variants. In GWAS data, genetically altered concentration of 27 protein biomarkers was associated with eGFR (P < 9.5 x 10^-5). UMOD was the strongest signal, a positive control of the analysis. Six of the significant biomarkers were previously identified in GWAS; 12 were in identified loci but the causal gene under the GWAS peak was unknown; and 9 loci were unidentified in GWAS. Novel biomarker associations with eGFR include interesting biological candidates such as inhibin beta chain C, a subunit of activins, and proteinase-3, the antigen in PR3-ANCA vasculitis.

Conclusion

Using a proteo-genomic association study, 27 biomarkers whose genetically predicted concentration were causally associated with changes in kidney function and risk of kidney disease including interesting biological candidates.

Funding

• Commercial Support –