PubMed ID: 40323663
Author(s): Cole JB, Dahlstrom EH, Fermin D, Gupta Y, Hill C, Smyth LJ, Liu H, Kreienkamp RJ, Pezzolesi MG, Cao JJ, Valo E, Chen WM, Onengut-Gumuscu S, Rich SS, Brennan EP, Andrews D, Kennedy C, Gu HF, Stechemesser L, Weitgasser R, Sokolovska J, Radzeviciene L, Verkauskiene R, Panduru NM, Rossing P, Ahluwalia TS, Zerbini G, Marre M, Hadjadj S, Costacou T, Miller RG, Klein BE, Lee KE, Snell-Bergeon JK, Caramori ML, Mauer M, Brismar K, Bjornstad P, McKnight AJ, McKay G, Nair V, Salem RM, Groop PH, Godson C, Susztak K, Kretzler M, Maxwell AP, Krolewski A, Paterson A, Sandholm-Lafferre N, Florez JC, Hirschhorn JN. Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci. J Am Soc Nephrol. 2025 May 5. doi: 10.1681/ASN.0000000718. Online ahead of print. PMID 40323663
Journal: Journal Of The American Society Of Nephrology : Jasn, May 2025
BACKGROUND Diabetic kidney disease (DKD) is a serious diabetes complication caused by both environmental and genetic risk factors. Previous genome-wide association studies (GWAS) have identified several loci associated with kidney function and kidney disease in the general population and, to a lesser extent, in diabetes.
METHODS To uncover the genetic factors driving diabetes-induced kidney function, we conducted a series of GWAS meta-analyses of estimated glomerular filtration rate (eGFR) in 17,267 individuals with type 1 diabetes and 35,264 with type 2 diabetes (52,531 total), utilizing multiple well characterized cohorts of type 1 diabetes DKD and data from the UK Biobank and SUMMIT Consortium. We further accounted for DKD case/control status, diabetes duration and subtype, body mass index, glycated hemoglobin levels, and the relationship between eGFR and albuminuria.
RESULTS GWAS identified 13 loci associated with eGFR (P<5×10-8), with five loci (candidate genes: HIPK3, TRIM5, RORA, ERBB4, and BCL6/LPP) not associated or were in opposite directions as compared to eGFR in the general population. Four candidate genes (HIPK3, BCL6, LPP, and RORA) demonstrated evidence of differential expression in kidney compartments and cells among subgroups with DKD or diabetes versus controls. Lead SNPs rs8027829 (RORA) and rs76300256 (BCL6/LPP) were methylation quantitative trait loci in whole blood and kidney tissue, respectively, and rs76300256 and its related CpGs all cluster in a kidney enhancer.
CONCLUSIONS Our integrated approach identified candidate genes with diabetes-specific effects on kidney function.
Copyright © 2025 by the American Society of Nephrology.