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

著者: Mathias Gorski, Bettina Jung, Yong Li, Pamela R. Matías‐García, 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. 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, André 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 Köenig, 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 G. Rots, Harold Snieder, Morris A. Swertz, Bruce H. R. Wolffenbuttel, Cisca Wijmenga, Gonçalo R. Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. 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 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 Preuß, Bruce M. Psaty, Laura M. Raffield, Olli T. Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth 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, Mélanie Waldenberger, Lars Wallentin, Dawn 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 - Kidney International 2020 被引用: 99

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.