Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Lifelines cohort study, Mathias Gorski, Bettina Jung, Yong Li, Pamela R Matias-Garcia, Matthias Wuttke, Stefan Coassin, Chris H L Thio, Marcus E Kleber, Thomas W Winkler, Veronika Wanner, Jin-Fang Chai, Audrey Y Chu, Massimiliano Cocca, Mary F Feitosa, Sahar Ghasemi, Anselm Hoppmann, Katrin Horn, Man Li, Teresa NutileMarkus Scholz, Karsten B Sieber, Alexander Teumer, Adrienne Tin, Judy Wang, Bamidele O Tayo, Tarunveer S Ahluwalia, Peter Almgren, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Robert J Carroll, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Josef Coresh, Martin H de Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Nina Hutri-Kähönen, Mika Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Pashupati P Mishra, Nina Mononen, Kjell Nikus

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Abstract

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.

Original languageEnglish
Pages (from-to)926-939
JournalKIDNEY INTERNATIONAL
Volume99
Issue number4
Early online date30 Oct 2020
DOIs
Publication statusPublished - 1 Apr 2021
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 2

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