Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
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 ass...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2021
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| In: |
Kidney international
Year: 2020, Volume: 99, Issue: 4, Pages: 926-939 |
| ISSN: | 1523-1755 |
| DOI: | 10.1016/j.kint.2020.09.030 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.kint.2020.09.030 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0085253820312394 
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| Author Notes: | 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, Behrooz Z. Alizadeh, H. Marike Boezen, Lude Franke, Pim van der Harst, Gerjan Navis, Marianne Rots, Harold Snieder, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, John D. Overton, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Jeffrey G. Reid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, 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 and Iris M. Heid |
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| 245 | 1 | 0 | |a Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline |c 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, Behrooz Z. Alizadeh, H. Marike Boezen, Lude Franke, Pim van der Harst, Gerjan Navis, Marianne Rots, Harold Snieder, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, John D. Overton, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Jeffrey G. Reid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, 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 and Iris M. Heid |
| 264 | 1 | |c 2021 | |
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| 500 | |a Published online 31 October 2020 | ||
| 500 | |a Gesehen am 03.05.2021 | ||
| 520 | |a 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. | ||
| 534 | |c 2020 | ||
| 650 | 4 | |a acute kidney injury | |
| 650 | 4 | |a end-stage kidney disease | |
| 650 | 4 | |a genome-wide association study | |
| 650 | 4 | |a rapid eGFRcrea decline | |
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