학술논문
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
Document Type
article
Author
Gorski, Mathias; Jung, Bettina; Li, Yong; Matias-Garcia, Pamela R; Wuttke, Matthias; Coassin, Stefan; Thio, Chris HL; Kleber, Marcus E; Winkler, Thomas W; Wanner, Veronika; Chai, Jin-Fang; Chu, Audrey Y; Cocca, Massimiliano; Feitosa, Mary F; Ghasemi, Sahar; Hoppmann, Anselm; Horn, Katrin; Li, Man; Nutile, Teresa; Scholz, Markus; Sieber, Karsten B; Teumer, Alexander; Tin, Adrienne; Wang, Judy; Tayo, Bamidele O; Ahluwalia, Tarunveer S; Almgren, Peter; Bakker, Stephan JL; Banas, Bernhard; Bansal, Nisha; Biggs, Mary L; Boerwinkle, Eric; Bottinger, Erwin P; Brenner, Hermann; Carroll, Robert J; Chalmers, John; Chee, Miao-Li; Chee, Miao-Ling; Cheng, Ching-Yu; Coresh, Josef; de Borst, Martin H; Degenhardt, Frauke; Eckardt, Kai-Uwe; Endlich, Karlhans; Franke, Andre; Freitag-Wolf, Sandra; Gampawar, Piyush; Gansevoort, Ron T; Ghanbari, Mohsen; Gieger, Christian; Hamet, Pavel; Ho, Kevin; Hofer, Edith; Holleczek, Bernd; Foo, Valencia Hui Xian; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Ikram, M Arfan; Josyula, Navya Shilpa; Kähönen, Mika; Khor, Chiea-Chuen; Koenig, Wolfgang; Kramer, Holly; Krämer, Bernhard K; Kühnel, Brigitte; Lange, Leslie A; Lehtimäki, Terho; Lieb, Wolfgang; Loos, Ruth JF; Lukas, Mary Ann; Lyytikäinen, Leo-Pekka; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Milaneschi, Yuri; Mishra, Pashupati P; Mononen, Nina; Mychaleckyj, Josyf C; Nadkarni, Girish N; Nauck, Matthias; Nikus, Kjell; Ning, Boting; Nolte, Ilja M; O’Donoghue, Michelle L; Orho-Melander, Marju; Pendergrass, Sarah A; Penninx, Brenda WJH; Preuss, Michael H; Psaty, Bruce M; Raffield, Laura M; Raitakari, Olli T; Rettig, Rainer; Rheinberger, Myriam; Rice, Kenneth M; Rosenkranz, Alexander R; Rossing, Peter; Rotter, Jerome I; Sabanayagam, Charumathi; Schmidt, Helena; Schmidt, Reinhold
Source
Kidney International. 99(4)
Subject
Language
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.