Journal Article

DKFZ-2020-02347

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Gorski, M. ; Jung, B. ; Li, Y. ; Matias-Garcia, P. R. ; Wuttke, M. ; Coassin, S. ; Thio, C. H. L. ; Kleber, M. E. ; Winkler, T. W. ; Wanner, V. ; Chai, J.-F. ; Chu, A. Y. ; Cocca, M. ; Feitosa, M. F. ; Ghasemi, S. ; Hoppmann, A. ; Horn, K. ; Li, M. ; Nutile, T. ; Scholz, M. ; Sieber, K. B. ; Teumer, A. ; Tin, A. ; Wang, J. ; Tayo, B. O. ; Ahluwalia, T. S. ; Almgren, P. ; Bakker, S. J. L. ; Banas, B. ; Bansal, N. ; Biggs, M. L. ; Boerwinkle, E. ; Bottinger, E. P. ; Brenner, H.DKFZ* ; Carroll, R. J. ; Chalmers, J. ; Chee, M.-L. ; Chee, M.-L. ; Cheng, C.-Y. ; Coresh, J. ; de Borst, M. H. ; Degenhardt, F. ; Eckardt, K.-U. ; Endlich, K. ; Franke, A. ; Freitag-Wolf, S. ; Gampawar, P. ; Gansevoort, R. T. ; Ghanbari, M. ; Gieger, C. ; Hamet, P. ; Ho, K. ; Hofer, E. ; Holleczek, B.DKFZ* ; Xian Foo, V. H. ; Hutri-Kähönen, N. ; Hwang, S.-J. ; Ikram, M. A. ; Josyula, N. S. ; Kähönen, M. ; Khor, C.-C. ; Koenig, W. ; Kramer, H. ; Krämer, B. K. ; Kühnel, B. ; Lange, L. A. ; Lehtimäki, T. ; Lieb, W. ; study, L. c. (Collaboration Author) ; Center, R. G. (Collaboration Author) ; Loos, R. J. F. ; Lukas, M. A. ; Lyytikäinen, L.-P. ; Meisinger, C. ; Meitinger, T. ; Melander, O. ; Milaneschi, Y. ; Mishra, P. P. ; Mononen, N. ; Mychaleckyj, J. C. ; Nadkarni, G. N. ; Nauck, M. ; Nikus, K. ; Ning, B. ; Nolte, I. M. ; O'Donoghue, M. L. ; Orho-Melander, M. ; Pendergrass, S. A. ; Penninx, B. W. J. H. ; Preuss, M. H. ; Psaty, B. M. ; Raffield, L. M. ; Raitakari, O. T. ; Rettig, R. ; Rheinberger, M. ; Rice, K. M. ; Rosenkranz, A. R. ; Rossing, P. ; Rotter, J. I. ; Sabanayagam, C. ; Schmidt, H. ; Schmidt, R. ; Schöttker, B.DKFZ* ; Schulz, C.-A. ; Sedaghat, S. ; Shaffer, C. M. ; Strauch, K. ; Szymczak, S. ; Taylor, K. D. ; Tremblay, J. ; Chaker, L. ; van der Harst, P. ; van der Most, P. J. ; Verweij, N. ; Völker, U. ; Waldenberger, M. ; Wallentin, L. ; Waterworth, D. M. ; White, H. D. ; Wilson, J. G. ; Wong, T.-Y. ; Woodward, M. ; Yang, Q. ; Yasuda, M. ; Yerges-Armstrong, L. M. ; Zhang, Y. ; Snieder, H. ; Wanner, C. ; Böger, C. A. ; Köttgen, A. ; Kronenberg, F. ; Pattaro, C. ; Heid, I. M.

2021
Elsevier New York, NY

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Please use a persistent id in citations: 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.

Note: 2021 Apr;99(4):926-939

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2021

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