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

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 Böttinger, 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-Kahonen, Shih-Jen Hwang, M. Arfan Ikram, Navya Shilpa Josyula, Mika Kahonen, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K. Kraemer, Brigitte Kuehnel, Leslie A. Lange, Terho Lehtimaki, Wolfgang Lieb, Ruth J. F. Loos, Mary Ann Lukas, Leo-Pekka Lyytikainen, 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 Rotter, Charumathi Sabanayagam, Helena Schmidt, Reinhold Schmidt, Ben Schoettker, 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 Voelker, 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. Boger, Anna Kottgen, Florian Kronenberg, Cristian Pattaro, Iris M. Heid

  • 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/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) 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 (nearRapid 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/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) 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.show moreshow less

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Author details:Mathias GorskiORCiD, Bettina Jung, Yong Li, Pamela R. Matias-Garcia, Matthias Wuttke, Stefan CoassinORCiD, 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 BöttingerGND, Hermann BrennerORCiD, Robert J. Carroll, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu ChengORCiD, Josef Coresh, Martin H. de Borst, Frauke DegenhardtORCiD, Kai-Uwe Eckardt, Karlhans EndlichORCiD, Andre FrankeORCiD, Sandra Freitag-Wolf, Piyush GampawarORCiD, Ron T. Gansevoort, Mohsen GhanbariORCiD, Christian Gieger, Pavel Hamet, Kevin Ho, Edith Hofer, Bernd Holleczek, Valencia Hui Xian Foo, Nina Hutri-Kahonen, Shih-Jen Hwang, M. Arfan Ikram, Navya Shilpa Josyula, Mika KahonenORCiD, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K. Kraemer, Brigitte Kuehnel, Leslie A. Lange, Terho Lehtimaki, Wolfgang Lieb, Ruth J. F. Loos, Mary Ann Lukas, Leo-Pekka Lyytikainen, Christa Meisinger, Thomas Meitinger, Olle MelanderORCiD, 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 Rotter, Charumathi Sabanayagam, Helena Schmidt, Reinhold Schmidt, Ben Schoettker, 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 Voelker, Melanie Waldenberger, Lars Wallentin, Dawn M. Waterworth, Harvey D. White, James G. Wilson, Tien-Yin Wong, Mark WoodwardORCiD, Qiong Yang, Masayuki Yasuda, Laura M. Yerges-ArmstrongORCiD, Yan Zhang, Harold Snieder, Christoph Wanner, Carsten A. Boger, Anna Kottgen, Florian KronenbergORCiD, Cristian Pattaro, Iris M. Heid
DOI:https://doi.org/10.1016/j.kint.2020.09.030
ISSN:0085-2538
ISSN:1523-1755
Pubmed ID:https://pubmed.ncbi.nlm.nih.gov/33137338
Title of parent work (English):Kidney international : official journal of the International Society of Nephrology
Publisher:Elsevier
Place of publishing:New York
Publication type:Article
Language:English
Date of first publication:2020/10/31
Publication year:2020
Creating corporation:Lifelines Cohort Study<br /> Regeneron Genetics Ctr
Release date:2022/11/07
Tag:acute kidney injury; end-stage kidney disease; genome-wide association; rapid eGFRcrea decline; study
Volume:99
Issue:4
Number of pages:14
First page:926
Last Page:939
Organizational units:Digital Engineering Fakultät / Hasso-Plattner-Institut für Digital Engineering GmbH
DDC classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Peer review:Referiert
Publishing method:Open Access / Bronze Open-Access
License (German):License LogoCC-BY-NC-ND - Namensnennung, nicht kommerziell, keine Bearbeitungen 4.0 International
External remark:Zweitveröffentlichung in der Schriftenreihe Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät ; 19
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