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

Gorski M, Jung B, Li Y, Matias-Garcia PR, Wuttke M, Coassin S, Thio CH, Kleber ME, Winkler TW, Wanner V, Chai JF, Chu AY, Cocca M, Feitosa MF, Ghasemi S, Hoppmann A, Horn K, Li M, Nutile T, Scholz M, Sieber KB, Teumer A, Tin A, Wang J, Tayo BO, Ahluwalia TS, Almgren P, Bakker SJ, Banas B, Bansal N, Biggs ML, Boerwinkle E, Bottinger EP, Brenner H, Carroll RJ, Chalmers J, Chee ML, Chee ML, Cheng CY, Coresh J, de Borst MH, Degenhardt F, Eckardt KU, Endlich K, Franke A, Freitag-Wolf S, Gampawar P, Gansevoort RT, Ghanbari M, Gieger C, Hamet P, Ho K, Hofer E, Holleczek B, Xian Foo VH, Hutri-Kähönen N, Hwang SJ, Ikram MA, Josyula NS, Kähönen M, Khor CC, Koenig W, Kramer H, Krämer BK, Kühnel B, Lange LA, Lehtimäki T, Lieb W, Alizadeh BZ, Boezen HM, Franke L, van der Harst P, Navis G, Rots M, Snieder H, Swertz M, Wolffenbuttel BH, Wijmenga C, Abecasis G, Baras A, Cantor M, Coppola G, Economides A, Lotta LA, Overton JD, Reid JG, Shuldiner A, Beechert C, Forsythe C, Fuller ED, Gu Z, Lattari M, Lopez A, Schleicher TD, Padilla MS, Toledo K, Widom L, Wolf SE, Pradhan M, Manoochehri K, Ulloa RH, Bai X, Balasubramanian S, Barnard L, Blumenfeld A, Eom G, Habegger L, Hawes A, Khalid S, Maxwell EK, Salerno W, Staples JC, Jones MB, Mitnaul LJ, Loos RJ, Lukas MA, Lyytikäinen LP, Meisinger C, Meitinger T, Melander O, Milaneschi Y, Mishra PP, Mononen N, Mychaleckyj JC, Nadkarni GN, Nauck M, Nikus K, Ning B, Nolte IM, O'Donoghue ML, Orho-Melander M, Pendergrass SA, Penninx BW, Preuss MH, Psaty BM, Raffield LM, Raitakari OT, Rettig R, Rheinberger M, Rice KM, Rosenkranz AR, Rossing P, Rotter JI, Sabanayagam C, Schmidt H, Schmidt R, Schöttker B, Schulz CA, Sedaghat S, Shaffer CM, Strauch K, Szymczak S, Taylor KD, Tremblay J, Chaker L, van der Most PJ, Verweij N, Völker U, Waldenberger M, Wallentin L, Waterworth DM, White HD, Wilson JG, Wong TY, Woodward M, Yang Q, Yasuda M, Yerges-Armstrong LM, Zhang Y, Wanner C, Böger CA, Köttgen A, Kronenberg F, Pattaro C, Heid IM (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1016/j.kint.2020.09.030

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.

Authors with CRIS profile

Involved external institutions

Christian-Albrechts-Universität zu Kiel Germany (DE) Deutsches Herzzentrum München Germany (DE) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Universitätsklinikum Regensburg Germany (DE) Division of Biomedical Informatics & Personalized Medicine United States (USA) (US) Medizinische Universität Graz Austria (AT) Fimlab Laboratories Finland (FI) Universitätsklinikum Mannheim Germany (DE) National University of Singapore (NUS) Singapore (SG) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Universität Regensburg Germany (DE) Universität Leipzig Germany (DE) Merck & Co., Inc. / Merck Sharp & Dohme Corp (MSD) United States (USA) (US) Albert-Ludwigs-Universität Freiburg Germany (DE) GlaxoSmithKline Research and Development United States (USA) (US) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) National University Health System (NUHS) Singapore (SG) Institute of genetics and biophysics "Adriano Buzzati Traverso" (IGB) Italy (IT) I.R.C.C.S. materno infantile Burlo Garofolo Italy (IT) Medizinische Universität Innsbruck Austria (AT) Icahn School of Medicine at Mount Sinai United States (USA) (US) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) Finland (FI) Erasmus University Medical Center (MC) Netherlands (NL) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of Virginia (UVA) United States (USA) (US) University of Mississippi Medical Center United States (USA) (US) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Geisinger Health System United States (USA) (US) Framingham Heart Study United States (USA) (US) Lund University / Lunds universitet Sweden (SE) University of Washington United States (USA) (US) Washington University in St. Louis United States (USA) (US) Vanderbilt University United States (USA) (US) eurac research Italy (IT) Steno Diabetes Center Denmark (DK) Centre hospitalier de l'Université de Montréal (CHUM) Canada (CA) Brigham and Women's Hospital (BWH) United States (USA) (US) Harbor–UCLA Medical Center United States (USA) (US) University of New South Wales (UNSW) Australia (AU) Universitätsklinikum Würzburg Germany (DE) Auckland City Hospital New Zealand (NZ) Uppsala University Sweden (SE) University of North Carolina at Chapel Hill United States (USA) (US) Johns Hopkins University (JHU) United States (USA) (US) Loyola University Chicago United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Kidney Health Research Institute (KHRI) United States (USA) (US) University of Utah United States (USA) (US) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) Finland (FI)

How to cite

APA:

Gorski, M., Jung, B., Li, Y., Matias-Garcia, P.R., Wuttke, M., Coassin, S.,... Heid, I.M. (2021). Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. Kidney International. https://doi.org/10.1016/j.kint.2020.09.030

MLA:

Gorski, Mathias, et al. "Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline." Kidney International (2021).

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