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

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作   者：

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;  Foo, Valencia Hui Xian;  Hutri-Kahonen, Nina;  Hwang, Shih-Jen;  Ikram, M. Arfan;  Josyula, Navya Shilpa;  Kahonen, Mika;  Khor, Chiea-Chuen;  Koenig, Wolfgang;  Kramer, Holly;  Kraemer, Bernhard K.;  Kuehnel, Brigitte;  Lange, Leslie A.;  Lehtimaki, Terho;  Lieb, Wolfgang;  Loos, Ruth J. F.;  Lukas, Mary Ann;  Lyytikainen, 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;  Schoettker, Ben;  Schulz, Christina-Alexandra; 

作者机构：

Univ Groningen;  Singapore;  Dept Internal Med;  Univ Mississippi;  Memory Impairment & Neurodegenerat Dementia MIND;  Hypertens & Cardiovasc Dis;  Cardiovasc Hlth Res Unit;  Univ Texas Hlth Sci Ctr Houston;  Dept Clin Physiol;  Seattle;  Franz Josef Strauss Allee 11;  Diabet & Cardiovasc Dis Genet Epidemiol;  New York;  Amsterdam Publ Hlth;  Dept Hlth Serv;  Fimlab Labs;  Natl Univ Singapore;  Helmholtz Zentrum Munchen;  Anschutz Med Campus;  St Louis;  Dept Clin Sci Malmo;  MD USA;  Inst Epidemiol;  TX 77030 USA;  Netherlands;  Amsterdam;  Freiburg;  Inst Mol Biol & Biochem;  IRCCS Burlo Garofolo;  IL USA;  Tampere Univ Hosp;  Maywood;  MA 02115 USA;  Human Genet Ctr;  Leipzig;  Finland;  Saw Swee Hock Sch Publ Hlth;  Berlin;  Merck & Co Inc;  Jackson;  Inst Genet Epidemiol;  Sch Med;  Ctr Publ Hlth Genom;  Dept Nephrol & Med Intens Care;  GlaxoSmithKline;  Biomed & Translat Informat Inst;  Australia;  Genet;  Div Nephrol;  Geisinger;  Inst Clin Mol Biol;  Tampere;  Nashville;  Res Unit Mol Epidemiol;  Inst Med Informat Stat & Epidemiol;  NC USA;  Sch Publ Hlth;  Univ Colorado Denver;  Framingham;  CNR;  Dept Epidemiol;  Dept Biostat;  Natl Univ Hlth Syst;  Dept Med;  Christian AlbrechtsUniv Kiel;  Clin Div Neurogeriatr;  Baltimore;  Dept Cardiol;  Med Fac Mannheim;  NY 10029 USA;  Dept Psychiat;  Chapel Hill;  Turku;  NM USA;  Greifswald;  Dept Publ Hlth Sci;  Inst Translat Genom & Populat Sci;  Innsbruck;  Germany;  Singapore Natl Eye Ctr;  CHUM;  VA USA;  Harbor UCLA Med Ctr;  Montreal;  Lund Univ;  Boston;  Tech Univ Munich;  Univ N Carolina;  George Inst Global Hlth;  Deutsch Herzzentrum Munchen;  Human Genet;  Dept Biomed Informat;  Amsterdam UMC;  Charlottesville;  WA 98195 USA;  Univ Freiburg;  Kenilworth;  Rotterdam;  Dept Genet & Pharmacol;  Turku Univ Hosp;  Groningen;  Houston;  Aurora;  Albuquerque;  Div Nephrol & Hypertens;  Dept Neurol;  Washington Univ;  MS 39216 USA;  PQ;  Med Ctr;  Dept Genet;  MO 63110 USA;  NHLBIs Framingham Heart Study;  PA USA;  Collegeville;  Univ Utah;  Div Clin Epidemiol & Aging Res;  Steno Diabet Ctr Copenhagen;  UT 84112 USA;  Fac Med;  Heidelberg Univ;  Salt Lake City;  Karlsburg;  Univ New South Wales;  Ctr Mol Med;  75 Francis St;  Dept Biometry Epidemiol & Med Bioinformat;  Brigham & Womens Hosp;  Cardiovasc Div;  TN USA;  Italy;  Div Biomed Informat & Personalized Med;  Univ Med Ctr Rotterdam;  Lundquist Inst Biomed Innovat;  Rockville;  German Res Ctr Environm Hlth;  Dept Med Nephrol Hypertensiol Rheumatol Endocrino;  Inst Maternal & Child Hlth;  Gentofte;  Univ Leipzig;  Boston Univ;  Cardiovasc Hlth Res Unit;  Dept Clin Chem;  Univ Virginia;  Med Univ Innsbruck;  German Canc Res Ctr;  Sweden;  Mannheim;  Neuherberg;  NJ USA;  Geisinger Res;  Inst Community Med;  NSW;  Kiel;  Sydney;  Div Stat Genom;  MA USA;  Dept Nephrol;  Partner Site Greifswald;  Montreal Univ Hosp Res Ctr;  Univ Washington;  Graz;  Vanderbilt Univ;  Partner Site Munich Heart Alliance;  Inst Physiol;  Univ Med Ctr Groningen;  DZHK German Ctr Cardiovasc Res;  Danville;  Med Univ Graz;  Target Sci Genet;  Naples;  Dept Clin Physiol & Nucl Med;  Inst Genet & Biophys Adriano Buzzati Traverso;  D-93053 Regensburg;  Johns Hopkins Bloomberg Sch Publ Hlth;  Charite Univ Med Berlin;  Erasmus MC;  Loyola Univ Chicago;  Munich;  Singapore Eye Res Inst;  Vrije Univ;  Univ Hosp Regensburg;  Canada;  Independent Res Grp Clin Epidemiol;  Trieste;  Charles Bronfman Inst Personalized Med;  Malmo;  Icahn Sch Med Mt Sinai;  Inst Med Informat & Stat;  WA USA;  Austria;  Univ Med Greifswald;  Univ Hosp Schleswig Holstein;  Dept Genet Epidemiol;  Univ Regensburg;  Univ Kiel;  Heidelberg;  Dept Pediat;  Kidney Hlth Res Inst KHRI;  Denmark; 

关键词：

end-stage kidney disease;  genome-wide association study;  rapid eGFRcrea decline;  acute kidney injury; 

期刊名称：

Kidney international.

i s s n：

0085-2538

年卷期：

2021 年 99 卷 4 期

页   码：

926-939

页   码：

摘   要：

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/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) 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.