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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
Tekijät: Gorski Mathias, Jung Bettina, Li Yong, Matias-Garcia Pamela R., Wuttke Matthias, Coassin Stefan, Thio Chris H.L., 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 J.L., 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, Xian Foo Valencia Hui, 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; Lifelines Cohort Study, Regeneron Genetics Center: Loos Ruth J.F., 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 W.J.H., 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, Schöttker Ben, Schulz Christina-Alexandra, Sedaghat Sanaz, Shaffer Christian M., Strauch Konstantin, Szymczak Silke, Taylor Kent D., Tremblay Johanne, Chaker Layal, van der Harst Pim, van der Most Peter J., Verweij Niek, Völker Uwe, Waldenberger Melanie, Wallentin Lars, Waterworth Dawn M., White Harvey D., Wilson James G., Wong Tien-Yin, Woodward Mark, Yang Qiong, Yasuda Masayuki, Yerges-Armstrong Laura M., Zhang Yan, Snieder Harold, Wanner Christoph, Böger Carsten A., Köttgen Anna, Kronenberg Florian, Pattaro Cristian, Heid Iris M.
Kustantaja: Elsevier
Julkaisuvuosi: 2021
Journal: Kidney International
Vuosikerta: 99
Numero: 4
Aloitussivu: 926
Lopetussivu: 939
eISSN: 1523-1755
DOI: https://doi.org/10.1016/j.kint.2020.09.030
Verkko-osoite: https://www.sciencedirect.com/science/article/pii/S0085253820312394?via%3Dihub
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/51844656
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
