TY - JOUR
T1 - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
AU - Lifelines Cohort Study
AU - Gorski, Mathias
AU - Jung, Bettina
AU - Li, Yong
AU - Matias-Garcia, Pamela R
AU - Wuttke, Matthias
AU - Coassin, Stefan
AU - Thio, Chris H L
AU - Kleber, Marcus E
AU - Winkler, Thomas W
AU - Wanner, Veronika
AU - Chai, Jin-Fang
AU - Chu, Audrey Y
AU - Cocca, Massimiliano
AU - Feitosa, Mary F
AU - Ghasemi, Sahar
AU - Hoppmann, Anselm
AU - Horn, Katrin
AU - Li, Man
AU - Nutile, Teresa
AU - Scholz, Markus
AU - Sieber, Karsten B
AU - Teumer, Alexander
AU - Tin, Adrienne
AU - Wang, Judy
AU - Tayo, Bamidele O
AU - Ahluwalia, Tarunveer S
AU - Almgren, Peter
AU - Bakker, Stephan J L
AU - Banas, Bernhard
AU - Bansal, Nisha
AU - Biggs, Mary L
AU - Boerwinkle, Eric
AU - Bottinger, Erwin P
AU - Brenner, Hermann
AU - Carroll, Robert J
AU - Chalmers, John
AU - Chee, Miao-Li
AU - Chee, Miao-Ling
AU - Cheng, Ching-Yu
AU - Coresh, Josef
AU - de Borst, Martin H
AU - Degenhardt, Frauke
AU - Gansevoort, Ron T
AU - Nolte, Ilja M
AU - Penninx, Brenda W J H
AU - van der Harst, Pim
AU - van der Most, Peter J
AU - Verweij, Niek
AU - Zhang, Yan
AU - Snieder, Harold
N1 - Copyright © 2020. Published by Elsevier Inc.
PY - 2020
Y1 - 2020
N2 - Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
AB - Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
U2 - 10.1016/j.kint.2020.09.030
DO - 10.1016/j.kint.2020.09.030
M3 - Article
C2 - 33137338
JO - Kidney International
JF - Kidney International
SN - 0085-2538
ER -