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

Lifelines Cohort Study; Regeneron Genetics Center

doi:10.1016/j.kint.2020.09.030

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

Lifelines Cohort Study, Regeneron Genetics Center

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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.

Original language	English (US)
Pages (from-to)	926-939
Number of pages	14
Journal	Kidney international
Volume	99
Issue number	4
DOIs	https://doi.org/10.1016/j.kint.2020.09.030
State	Published - Apr 1 2021
Externally published	Yes

Bibliographical note

Funding Information:
We thank Daniele Di Domizio (Eurac Research) and Randy R?ckner (University of Regensburg) for IT assistance. The University of Regensburg provided computing resources for the meta-analysis. We conducted this research using the UK Biobank resource under the application number 20272. General and study-specific acknowledgements and funding sources are provided in the Supplementary Material. MG, BJ, PRM-G, CAB, AK, FK, CP, and IMH wrote the manuscript. MG, MWu, AT, CAB, AK, and CP designed the study. BJ, MS, BOT, TSA, SJLB, BB, EB, HB, RJC, JChal, CC, JCo, MHdB, KEc, RTG, CG, PH, KeH, BH, MAI, MK?, CK, WKo, HKr, BKK, TL, RJFL, MAL, OM, YM, GNN, MLO, MO, SAP, BWJHP, BMP, OTR, RRe, MR, PR, CSa, HSc, RS, BS, KStr, PvdH, UV, LWal, DMW, HDW, JGW, TWo, MW, QY, MY, YZ, HSn, CAB, AK, FK, and CP managed an individual contributing study. MG, BJ, YL, MWu, CHLT, TW, VW, JChai, AC, MC, MF, SG, AH, KH, ML, TN, MS, KBS, AT, ATi, JW, BOT, TSA, PA, MLBig, RJC, JChal, MLiC, SF, MGh, PH, EH, SH, NSJ, CK, HKr, BK, LAL, LLy, PPM, NM, MN, BN, IMN, SAP, MHP, LMR, MR, KMR, CSc, SSe, SSz, JTr, PvdH, PJvdM, NV, MW, QY, LMY, CW, CAB, AK, CP, and IMH performed statistical methods and analysis. MG, YL, MWu, ST, MK, TW, VW, AC, MC, SG, AH, KH, ML, TN, MS, KBS, JW, TSA, PA, RJC, FD, AF, PG, PH, EH, NSJ, CK, LLy, YM, PPM, SAP, MHP, CSc, SSe, CMS, SSz, JTr, PJvdM, LMY, CW, CAB, and IMH performed bioinformatics. MG, BJ, YL, MWu, ST, TW, VW, MF, SG, KH, ML, MS, KBS, AT, BOT, TSA, JChal, KEn, MGh, CG, PH, KeH, SH, WKo, SAP, MR, SSe, JTr, LC, PvdH, NV, LWal, HDW, MW, MY, LMY, CAB, AK, CP, and IMH interpreted results. MK, MF, AT, EB, CC, AF, RTG, PH, MK?, CK, WKo, LAL, TL, LLy, TM, OM, YM, NM, JcM, MO, BWJHP, MHP, OTR, JIR, KDT, JTr, PvdH, UV, MWa, JGW, CW, CAB, and FK performed genotyping. MG, BJ, YL, PRM-G, MWu, ST, TW, VW, AC, MF, SG, AH, ML, TN, MS, KBS, AT, ATi, BOT, TSA, PA, SJLB, NB, MLBig, EPB, HB, JChal, JCo, MHdB, KEc, KEn, AF, PG, MGh, CG, PH, KeH, BH, NH, SH, MK?, WKo, HKr, BKK, BK, LAL, TL, WL, RJFL, LLy, CM, TM, OM, GNN, MN, KN, BN, IMN, MLO, MO, SAP, BWJHP, MHP, BMP, LMR, OTR, RRe, MR, KMR, AR, PR, CSa, BS, CSc, SSe, KStr, JTr, LC, PvdH, NV, UV, MWa, LWal, DMW, HDW, JGW, MW, QY, YZ, HSn, CAB, AK, FK, CP, and IMH critically reviewed the manuscript. BJ, EPB, HB, JChal, MLingC, CC, JCo, KEc, RTG, PH, VHXF, NH, MK?, TL, WL, CM, KN, MLO, SAP, BWJHP, OTR, MR, AR, PR, RS, LWal, HDW, JGW, TWo, MW, CAB, AK, and CP recruited subjects.

Funding Information:
MLBig reports grants from National Heart Lung Blood Institute during the conduct of the study. EB reports grants from the National Institute of Health (NIH), during the conduct of the study. RJC reports grants from the US NIH, during the conduct of the study. KEc reports grants from Astra Zeneca, Bayer, FMC, and Vifor, during the conduct of the study; personal fees from Akebia, Bayer, Boehringer Ingelheim, and Vifor; and grants from Amgen, outside the submitted work. KeH reports other from Sanofi Genzyme and Partners Healthcare, outside the submitted work. MK reports personal fees from Bayer, outside the submitted work. WKo reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb; and grants and nonfinancial support from Singulex, Abbott, Roche Diagnostics, and Beckmann, outside the submitted work. MAL reports to be employed by and stockholder of GlaxoSmithKline, outside the submitted work. JcM reports grants from the NIH, during the conduct of the study. GNN reports grants, personal fees, and nonfinancial support from RenalytixAI; personal fees and nonfinancial support from Pensieve Health; and personal fees from Reata, AstraZeneca, BioVie, and GLG Consulting, outside the submitted work. MLO reports grants from GlaxoSmithKline, during the conduct of the study; grants from Intarcia; grants and personal fees from Novartis and Amgen; and grants from AstraZeneca, outside the submitted work. BMP reports grants from the NIH during the conduct of the study; and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. PR reports grants and other from Astra Zeneca and Novo Nordisk; and other from Astellas, Bayer, Boehringer Ingelheim, Gilead, Merck, Sanofi, Eli Lilly, Mundipharma, and Vifor, outside the submitted work; all to Steno Diabetes Center Copenhagen. JIR reports grants from the NIH, during the conduct of the study. MS reports grants from Pfizer Inc., outside the submitted work. NV reports other from Regeneron Genetics Center and Genomics plc, outside the submitted work. LWal reports grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co., and Roche Diagnostics; and other from Abbott, outside the submitted work. CW reports grants from Boehringer-Ingelheim, Idorsia, and Sanofi-Genzyme; and personal fees from Boehringer Ingelheim, Eli-Lilly, Sanofi-Genzyme, Akebia, Mundipharma, MSD, AstraZeneca, and Bayer, from null, outside the submitted work. DMW reports at the time of contributing to this manuscript to be a full-time employee of GlaxoSmithKline. HDW reports grants and personal fees from Eli Lilly and Company, Omthera Pharmaceuticals, Eisai Inc., DalCor Pharma UK Inc., CSL Behring LLC, and American Regent; personal fees and nonfinancial support from AstraZeneca; grants, personal fees, and nonfinancial support from Sanofi-Aventis Australia Pty Ltd., Esperion Therapeutics Inc., and Sanofi-Aventis; and personal fees from Genentech, Inc., outside the submitted work. MW reports personal fees from Amgen and Kirin, outside the submitted work. LMY reports personal fees from GlaxoSmithKline, outside the submitted work. AC reports being employed by Merck & Co. during the conduct of the study and to be employed by GlaxoSmithKline, outside the submitted work. TWo reports grants from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, Bioepis, NMRC, and Novartis Singapore; personal fees from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, and Bioepis, during the conduct of the study; and personal fees from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, and Bioepis, and other from Plano EyRiS, outside the submitted work. JCo reports grants from the NIH and National Kidney Foundation, during the conduct of the study, and grants from the NIH and National Kidney Foundation, outside the submitted work. MN reports grants from Federal Ministry of Education and Research Germany, the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; personal fees from Becton Dickinson (BD); grants from Federal Ministry of Education and Research, Germany, European Union Interreg IVa; and personal fees from German Medical Association, German Centre for Cardiovascular Research (GCCR), and National Cohort, outside the submitted work. KBS reports being a full-time employee of GlaxoSmithKline plc. All other authors declared no competing interests.

Publisher Copyright:
© 2020 International Society of Nephrology

Keywords

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

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10.1016/j.kint.2020.09.030

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@article{ea227157aeaf41f2969d2ca58be06b5c,

title = "Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline",

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.",

keywords = "acute kidney injury, end-stage kidney disease, genome-wide association study, rapid eGFRcrea decline",

author = "{Lifelines Cohort Study} and {Regeneron Genetics Center} and Mathias Gorski and Bettina Jung and Yong Li and Matias-Garcia, {Pamela R.} and Matthias Wuttke and Stefan Coassin and Thio, {Chris H.L.} and Kleber, {Marcus E.} and Winkler, {Thomas W.} and Veronika Wanner and Chai, {Jin Fang} and Chu, {Audrey Y.} and Massimiliano Cocca and Feitosa, {Mary F.} and Sahar Ghasemi and Anselm Hoppmann and Katrin Horn and Man Li and Teresa Nutile and Markus Scholz and Sieber, {Karsten B.} and Alexander Teumer and Adrienne Tin and Judy Wang and Tayo, {Bamidele O.} and Ahluwalia, {Tarunveer S.} and Peter Almgren and Bakker, {Stephan J.L.} and Bernhard Banas and Nisha Bansal and Biggs, {Mary L.} and Eric Boerwinkle and Bottinger, {Erwin P.} and Hermann Brenner and Carroll, {Robert J.} and John Chalmers and Chee, {Miao Li} and Chee, {Miao Ling} and Cheng, {Ching Yu} and Josef Coresh and {de Borst}, {Martin H.} and Frauke Degenhardt and Eckardt, {Kai Uwe} and Karlhans Endlich and Andre Franke and Sandra Freitag-Wolf and Piyush Gampawar and Gansevoort, {Ron T.} and Mohsen Ghanbari and Sanaz Sedaghat",

note = "Funding Information: We thank Daniele Di Domizio (Eurac Research) and Randy R?ckner (University of Regensburg) for IT assistance. The University of Regensburg provided computing resources for the meta-analysis. We conducted this research using the UK Biobank resource under the application number 20272. General and study-specific acknowledgements and funding sources are provided in the Supplementary Material. MG, BJ, PRM-G, CAB, AK, FK, CP, and IMH wrote the manuscript. MG, MWu, AT, CAB, AK, and CP designed the study. BJ, MS, BOT, TSA, SJLB, BB, EB, HB, RJC, JChal, CC, JCo, MHdB, KEc, RTG, CG, PH, KeH, BH, MAI, MK?, CK, WKo, HKr, BKK, TL, RJFL, MAL, OM, YM, GNN, MLO, MO, SAP, BWJHP, BMP, OTR, RRe, MR, PR, CSa, HSc, RS, BS, KStr, PvdH, UV, LWal, DMW, HDW, JGW, TWo, MW, QY, MY, YZ, HSn, CAB, AK, FK, and CP managed an individual contributing study. MG, BJ, YL, MWu, CHLT, TW, VW, JChai, AC, MC, MF, SG, AH, KH, ML, TN, MS, KBS, AT, ATi, JW, BOT, TSA, PA, MLBig, RJC, JChal, MLiC, SF, MGh, PH, EH, SH, NSJ, CK, HKr, BK, LAL, LLy, PPM, NM, MN, BN, IMN, SAP, MHP, LMR, MR, KMR, CSc, SSe, SSz, JTr, PvdH, PJvdM, NV, MW, QY, LMY, CW, CAB, AK, CP, and IMH performed statistical methods and analysis. MG, YL, MWu, ST, MK, TW, VW, AC, MC, SG, AH, KH, ML, TN, MS, KBS, JW, TSA, PA, RJC, FD, AF, PG, PH, EH, NSJ, CK, LLy, YM, PPM, SAP, MHP, CSc, SSe, CMS, SSz, JTr, PJvdM, LMY, CW, CAB, and IMH performed bioinformatics. MG, BJ, YL, MWu, ST, TW, VW, MF, SG, KH, ML, MS, KBS, AT, BOT, TSA, JChal, KEn, MGh, CG, PH, KeH, SH, WKo, SAP, MR, SSe, JTr, LC, PvdH, NV, LWal, HDW, MW, MY, LMY, CAB, AK, CP, and IMH interpreted results. MK, MF, AT, EB, CC, AF, RTG, PH, MK?, CK, WKo, LAL, TL, LLy, TM, OM, YM, NM, JcM, MO, BWJHP, MHP, OTR, JIR, KDT, JTr, PvdH, UV, MWa, JGW, CW, CAB, and FK performed genotyping. MG, BJ, YL, PRM-G, MWu, ST, TW, VW, AC, MF, SG, AH, ML, TN, MS, KBS, AT, ATi, BOT, TSA, PA, SJLB, NB, MLBig, EPB, HB, JChal, JCo, MHdB, KEc, KEn, AF, PG, MGh, CG, PH, KeH, BH, NH, SH, MK?, WKo, HKr, BKK, BK, LAL, TL, WL, RJFL, LLy, CM, TM, OM, GNN, MN, KN, BN, IMN, MLO, MO, SAP, BWJHP, MHP, BMP, LMR, OTR, RRe, MR, KMR, AR, PR, CSa, BS, CSc, SSe, KStr, JTr, LC, PvdH, NV, UV, MWa, LWal, DMW, HDW, JGW, MW, QY, YZ, HSn, CAB, AK, FK, CP, and IMH critically reviewed the manuscript. BJ, EPB, HB, JChal, MLingC, CC, JCo, KEc, RTG, PH, VHXF, NH, MK?, TL, WL, CM, KN, MLO, SAP, BWJHP, OTR, MR, AR, PR, RS, LWal, HDW, JGW, TWo, MW, CAB, AK, and CP recruited subjects. Funding Information: MLBig reports grants from National Heart Lung Blood Institute during the conduct of the study. EB reports grants from the National Institute of Health (NIH), during the conduct of the study. RJC reports grants from the US NIH, during the conduct of the study. KEc reports grants from Astra Zeneca, Bayer, FMC, and Vifor, during the conduct of the study; personal fees from Akebia, Bayer, Boehringer Ingelheim, and Vifor; and grants from Amgen, outside the submitted work. KeH reports other from Sanofi Genzyme and Partners Healthcare, outside the submitted work. MK reports personal fees from Bayer, outside the submitted work. WKo reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb; and grants and nonfinancial support from Singulex, Abbott, Roche Diagnostics, and Beckmann, outside the submitted work. MAL reports to be employed by and stockholder of GlaxoSmithKline, outside the submitted work. JcM reports grants from the NIH, during the conduct of the study. GNN reports grants, personal fees, and nonfinancial support from RenalytixAI; personal fees and nonfinancial support from Pensieve Health; and personal fees from Reata, AstraZeneca, BioVie, and GLG Consulting, outside the submitted work. MLO reports grants from GlaxoSmithKline, during the conduct of the study; grants from Intarcia; grants and personal fees from Novartis and Amgen; and grants from AstraZeneca, outside the submitted work. BMP reports grants from the NIH during the conduct of the study; and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. PR reports grants and other from Astra Zeneca and Novo Nordisk; and other from Astellas, Bayer, Boehringer Ingelheim, Gilead, Merck, Sanofi, Eli Lilly, Mundipharma, and Vifor, outside the submitted work; all to Steno Diabetes Center Copenhagen. JIR reports grants from the NIH, during the conduct of the study. MS reports grants from Pfizer Inc., outside the submitted work. NV reports other from Regeneron Genetics Center and Genomics plc, outside the submitted work. LWal reports grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co., and Roche Diagnostics; and other from Abbott, outside the submitted work. CW reports grants from Boehringer-Ingelheim, Idorsia, and Sanofi-Genzyme; and personal fees from Boehringer Ingelheim, Eli-Lilly, Sanofi-Genzyme, Akebia, Mundipharma, MSD, AstraZeneca, and Bayer, from null, outside the submitted work. DMW reports at the time of contributing to this manuscript to be a full-time employee of GlaxoSmithKline. HDW reports grants and personal fees from Eli Lilly and Company, Omthera Pharmaceuticals, Eisai Inc., DalCor Pharma UK Inc., CSL Behring LLC, and American Regent; personal fees and nonfinancial support from AstraZeneca; grants, personal fees, and nonfinancial support from Sanofi-Aventis Australia Pty Ltd., Esperion Therapeutics Inc., and Sanofi-Aventis; and personal fees from Genentech, Inc., outside the submitted work. MW reports personal fees from Amgen and Kirin, outside the submitted work. LMY reports personal fees from GlaxoSmithKline, outside the submitted work. AC reports being employed by Merck & Co. during the conduct of the study and to be employed by GlaxoSmithKline, outside the submitted work. TWo reports grants from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, Bioepis, NMRC, and Novartis Singapore; personal fees from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, and Bioepis, during the conduct of the study; and personal fees from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, and Bioepis, and other from Plano EyRiS, outside the submitted work. JCo reports grants from the NIH and National Kidney Foundation, during the conduct of the study, and grants from the NIH and National Kidney Foundation, outside the submitted work. MN reports grants from Federal Ministry of Education and Research Germany, the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; personal fees from Becton Dickinson (BD); grants from Federal Ministry of Education and Research, Germany, European Union Interreg IVa; and personal fees from German Medical Association, German Centre for Cardiovascular Research (GCCR), and National Cohort, outside the submitted work. KBS reports being a full-time employee of GlaxoSmithKline plc. All other authors declared no competing interests. Publisher Copyright: {\textcopyright} 2020 International Society of Nephrology",

year = "2021",

month = apr,

day = "1",

doi = "10.1016/j.kint.2020.09.030",

language = "English (US)",

volume = "99",

pages = "926--939",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

AU - Lifelines Cohort Study

AU - Regeneron Genetics Center

AU - Gorski, Mathias

AU - Jung, Bettina

AU - Li, Yong

AU - Matias-Garcia, Pamela R.

AU - Wuttke, Matthias

AU - Coassin, Stefan

AU - Thio, Chris H.L.

AU - Kleber, Marcus E.

AU - Winkler, Thomas W.

AU - Wanner, Veronika

AU - Chai, Jin Fang

AU - Chu, Audrey Y.

AU - Cocca, Massimiliano

AU - Feitosa, Mary F.

AU - Ghasemi, Sahar

AU - Hoppmann, Anselm

AU - Horn, Katrin

AU - Li, Man

AU - Nutile, Teresa

AU - Scholz, Markus

AU - Sieber, Karsten B.

AU - Teumer, Alexander

AU - Tin, Adrienne

AU - Wang, Judy

AU - Tayo, Bamidele O.

AU - Ahluwalia, Tarunveer S.

AU - Almgren, Peter

AU - Bakker, Stephan J.L.

AU - Banas, Bernhard

AU - Bansal, Nisha

AU - Biggs, Mary L.

AU - Boerwinkle, Eric

AU - Bottinger, Erwin P.

AU - Brenner, Hermann

AU - Carroll, Robert J.

AU - Chalmers, John

AU - Chee, Miao Li

AU - Chee, Miao Ling

AU - Cheng, Ching Yu

AU - Coresh, Josef

AU - de Borst, Martin H.

AU - Degenhardt, Frauke

AU - Eckardt, Kai Uwe

AU - Endlich, Karlhans

AU - Franke, Andre

AU - Freitag-Wolf, Sandra

AU - Gampawar, Piyush

AU - Gansevoort, Ron T.

AU - Ghanbari, Mohsen

AU - Sedaghat, Sanaz

N1 - Funding Information: We thank Daniele Di Domizio (Eurac Research) and Randy R?ckner (University of Regensburg) for IT assistance. The University of Regensburg provided computing resources for the meta-analysis. We conducted this research using the UK Biobank resource under the application number 20272. General and study-specific acknowledgements and funding sources are provided in the Supplementary Material. MG, BJ, PRM-G, CAB, AK, FK, CP, and IMH wrote the manuscript. MG, MWu, AT, CAB, AK, and CP designed the study. BJ, MS, BOT, TSA, SJLB, BB, EB, HB, RJC, JChal, CC, JCo, MHdB, KEc, RTG, CG, PH, KeH, BH, MAI, MK?, CK, WKo, HKr, BKK, TL, RJFL, MAL, OM, YM, GNN, MLO, MO, SAP, BWJHP, BMP, OTR, RRe, MR, PR, CSa, HSc, RS, BS, KStr, PvdH, UV, LWal, DMW, HDW, JGW, TWo, MW, QY, MY, YZ, HSn, CAB, AK, FK, and CP managed an individual contributing study. MG, BJ, YL, MWu, CHLT, TW, VW, JChai, AC, MC, MF, SG, AH, KH, ML, TN, MS, KBS, AT, ATi, JW, BOT, TSA, PA, MLBig, RJC, JChal, MLiC, SF, MGh, PH, EH, SH, NSJ, CK, HKr, BK, LAL, LLy, PPM, NM, MN, BN, IMN, SAP, MHP, LMR, MR, KMR, CSc, SSe, SSz, JTr, PvdH, PJvdM, NV, MW, QY, LMY, CW, CAB, AK, CP, and IMH performed statistical methods and analysis. MG, YL, MWu, ST, MK, TW, VW, AC, MC, SG, AH, KH, ML, TN, MS, KBS, JW, TSA, PA, RJC, FD, AF, PG, PH, EH, NSJ, CK, LLy, YM, PPM, SAP, MHP, CSc, SSe, CMS, SSz, JTr, PJvdM, LMY, CW, CAB, and IMH performed bioinformatics. MG, BJ, YL, MWu, ST, TW, VW, MF, SG, KH, ML, MS, KBS, AT, BOT, TSA, JChal, KEn, MGh, CG, PH, KeH, SH, WKo, SAP, MR, SSe, JTr, LC, PvdH, NV, LWal, HDW, MW, MY, LMY, CAB, AK, CP, and IMH interpreted results. MK, MF, AT, EB, CC, AF, RTG, PH, MK?, CK, WKo, LAL, TL, LLy, TM, OM, YM, NM, JcM, MO, BWJHP, MHP, OTR, JIR, KDT, JTr, PvdH, UV, MWa, JGW, CW, CAB, and FK performed genotyping. MG, BJ, YL, PRM-G, MWu, ST, TW, VW, AC, MF, SG, AH, ML, TN, MS, KBS, AT, ATi, BOT, TSA, PA, SJLB, NB, MLBig, EPB, HB, JChal, JCo, MHdB, KEc, KEn, AF, PG, MGh, CG, PH, KeH, BH, NH, SH, MK?, WKo, HKr, BKK, BK, LAL, TL, WL, RJFL, LLy, CM, TM, OM, GNN, MN, KN, BN, IMN, MLO, MO, SAP, BWJHP, MHP, BMP, LMR, OTR, RRe, MR, KMR, AR, PR, CSa, BS, CSc, SSe, KStr, JTr, LC, PvdH, NV, UV, MWa, LWal, DMW, HDW, JGW, MW, QY, YZ, HSn, CAB, AK, FK, CP, and IMH critically reviewed the manuscript. BJ, EPB, HB, JChal, MLingC, CC, JCo, KEc, RTG, PH, VHXF, NH, MK?, TL, WL, CM, KN, MLO, SAP, BWJHP, OTR, MR, AR, PR, RS, LWal, HDW, JGW, TWo, MW, CAB, AK, and CP recruited subjects. Funding Information: MLBig reports grants from National Heart Lung Blood Institute during the conduct of the study. EB reports grants from the National Institute of Health (NIH), during the conduct of the study. RJC reports grants from the US NIH, during the conduct of the study. KEc reports grants from Astra Zeneca, Bayer, FMC, and Vifor, during the conduct of the study; personal fees from Akebia, Bayer, Boehringer Ingelheim, and Vifor; and grants from Amgen, outside the submitted work. KeH reports other from Sanofi Genzyme and Partners Healthcare, outside the submitted work. MK reports personal fees from Bayer, outside the submitted work. WKo reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb; and grants and nonfinancial support from Singulex, Abbott, Roche Diagnostics, and Beckmann, outside the submitted work. MAL reports to be employed by and stockholder of GlaxoSmithKline, outside the submitted work. JcM reports grants from the NIH, during the conduct of the study. GNN reports grants, personal fees, and nonfinancial support from RenalytixAI; personal fees and nonfinancial support from Pensieve Health; and personal fees from Reata, AstraZeneca, BioVie, and GLG Consulting, outside the submitted work. MLO reports grants from GlaxoSmithKline, during the conduct of the study; grants from Intarcia; grants and personal fees from Novartis and Amgen; and grants from AstraZeneca, outside the submitted work. BMP reports grants from the NIH during the conduct of the study; and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. PR reports grants and other from Astra Zeneca and Novo Nordisk; and other from Astellas, Bayer, Boehringer Ingelheim, Gilead, Merck, Sanofi, Eli Lilly, Mundipharma, and Vifor, outside the submitted work; all to Steno Diabetes Center Copenhagen. JIR reports grants from the NIH, during the conduct of the study. MS reports grants from Pfizer Inc., outside the submitted work. NV reports other from Regeneron Genetics Center and Genomics plc, outside the submitted work. LWal reports grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co., and Roche Diagnostics; and other from Abbott, outside the submitted work. CW reports grants from Boehringer-Ingelheim, Idorsia, and Sanofi-Genzyme; and personal fees from Boehringer Ingelheim, Eli-Lilly, Sanofi-Genzyme, Akebia, Mundipharma, MSD, AstraZeneca, and Bayer, from null, outside the submitted work. DMW reports at the time of contributing to this manuscript to be a full-time employee of GlaxoSmithKline. HDW reports grants and personal fees from Eli Lilly and Company, Omthera Pharmaceuticals, Eisai Inc., DalCor Pharma UK Inc., CSL Behring LLC, and American Regent; personal fees and nonfinancial support from AstraZeneca; grants, personal fees, and nonfinancial support from Sanofi-Aventis Australia Pty Ltd., Esperion Therapeutics Inc., and Sanofi-Aventis; and personal fees from Genentech, Inc., outside the submitted work. MW reports personal fees from Amgen and Kirin, outside the submitted work. LMY reports personal fees from GlaxoSmithKline, outside the submitted work. AC reports being employed by Merck & Co. during the conduct of the study and to be employed by GlaxoSmithKline, outside the submitted work. TWo reports grants from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, Bioepis, NMRC, and Novartis Singapore; personal fees from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, and Bioepis, during the conduct of the study; and personal fees from Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung, and Bioepis, and other from Plano EyRiS, outside the submitted work. JCo reports grants from the NIH and National Kidney Foundation, during the conduct of the study, and grants from the NIH and National Kidney Foundation, outside the submitted work. MN reports grants from Federal Ministry of Education and Research Germany, the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; personal fees from Becton Dickinson (BD); grants from Federal Ministry of Education and Research, Germany, European Union Interreg IVa; and personal fees from German Medical Association, German Centre for Cardiovascular Research (GCCR), and National Cohort, outside the submitted work. KBS reports being a full-time employee of GlaxoSmithKline plc. All other authors declared no competing interests. Publisher Copyright: © 2020 International Society of Nephrology

PY - 2021/4/1

Y1 - 2021/4/1

N2 - 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.

AB - 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.

KW - acute kidney injury

KW - end-stage kidney disease

KW - genome-wide association study

KW - rapid eGFRcrea decline

UR - http://www.scopus.com/inward/record.url?scp=85101404544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85101404544&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2020.09.030

DO - 10.1016/j.kint.2020.09.030

M3 - Article

C2 - 33137338

AN - SCOPUS:85101404544

SN - 0085-2538

VL - 99

SP - 926

EP - 939

JO - Kidney international

JF - Kidney international

IS - 4

ER -

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

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