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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • 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 Nutile
  • Markus 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
  • Karlhans Endlich
  • Andre Franke
  • Sandra Freitag-Wolf
  • Piyush Gampawar
  • Ron T Gansevoort
  • Mohsen Ghanbari
  • Peter Rossing
  • LifeLines Cohort study
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftKidney International
Vol/bind99
Udgave nummer4
Sider (fra-til)4, P926-939
ISSN0085-2538
DOI
StatusUdgivet - 1 apr. 2021

Bibliografisk note

Copyright © 2020. Published by Elsevier Inc.

ID: 61252057