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

Authors:
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, Christian Gieger, Pavel Hamet, Kevin Ho, Edith Hofer, Bernd Holleczek, Valencia Hui Xian Foo, Nina Hutri-Kähönen, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Mika Kähönen, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Leslie A Lange, Terho Lehtimäki, Wolfgang Lieb, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Josyf C Mychaleckyj, Girish N Nadkarni, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Michelle L O'Donoghue, Marju Orho-Melander, Sarah A Pendergrass, Brenda W J H Penninx, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth M Rice, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Charumathi Sabanayagam, Helena Schmidt, Reinhold Schmidt, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Konstantin Strauch, Silke Szymczak, Kent D Taylor, Johanne Tremblay, Layal Chaker, Pim van der Harst, Peter J van der Most, Niek Verweij, Uwe Völker, Melanie Waldenberger, Lars Wallentin, Dawn M Waterworth, Harvey D White, James G Wilson, Tien-Yin Wong, Mark Woodward, Qiong Yang, Masayuki Yasuda, Laura M Yerges-Armstrong, Yan Zhang, Harold Snieder, Christoph Wanner, Carsten A Böger, Anna Köttgen, Florian Kronenberg, Cristian Pattaro, Iris M Heid
Year of publication:
2020
Volume:
-
Issue:
-
Issn:
0085-2538
Journal title abbreviated:
KIDNEY INT
Journal title long:
Kidney international
Impact factor:
8.945
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.