Strong protective effect of the APOL1 p.N264K variant against G2-associated FSGS and kidney disease
Gupta, Y.; Friedman, D. J.; McNulty, M.; Khan, A.; Lane, B.; Wang, C.; Ke, J.; Jin, G.; Wooden, B.; Knob, A. L.; Lim, T. Y.; Appel, G. B.; Huggins, K.; Liu, L.; Mitrotti, A.; Stangl, M. C.; Bomback, A.; Westland, R.; Bodria, M.; Marasa, M.; Shang, N.; Cohen, D. J.; Crew, R. J.; Morello, W.; Canetta, P.; Radhakrishnan, J.; Martino, J.; Liu, Q.; Chung, W. K.; Espinoza, A.; Luo, Y.; Wei, W.-Q.; Feng, Q.; Weng, C.; Fang, Y.; Kullo, I. J.; Naderian, M.; Limdi, N.; Irvin, M. R.; Tiwari, H.; Mohan, S.; Rao, M.; Dube, G.; Chaudhary, N. S.; Gutierrez, O. M.; Judd, S. E.; Cushman, M.; Lange, L. A.; Lang
Show abstract
Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Genome-wide characterization of 54 urinary metabolites reveals molecular impact of kidney function 92%
- Exome-wide analysis of congenital kidney anomalies reveals new genes and shared architecture with developmental disorders 92%
- Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy 92%
Similar papers in this journal
Similar papers in this journal
- ATP-citrate lyase as a therapeutic target in chronic kidney disease: a Mendelian Randomization analysis 95%
- Phenotypic spectrum of FAM47E - SHROOM3 haplotype composition in a general population sample 94%
- Urine single cell RNA-sequencing in focal segmental glomerulosclerosis reveals inflammatory signatures in immune cells and podocytes 92%
Similar papers in this journal
- Urinary metabolite profiling identifies biomarkers for risk of progression of diabetic nephropathy in 2,670 individuals with type 1 diabetes 92%
- Precision medicine in Type 2 Diabetes: Targeting SGLT2-inhibitor Treatment For Kidney Protection 91%
- Spatial proteomics of human diabetic kidney disease, from health to class III 91%
Similar papers in this journal
- Renal Proximal Tubule Cell-specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed Western Diet 93%
- Antithrombin, protein C and protein S: Genome and transcriptome wide association studies identify 7 novel loci regulating plasma levels 92%
- Carotid intima-media thickness in UK Biobank: Identification of novel genome-wide loci, sex-specific effects and genetic correlations with obesity and glucometabolic traits. 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.