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

被引：58

作者：

Gorski, Mathias ^{[1
,2
,3
]}

Jung, Bettina ^{[3
]}

Li, Yong ^{[4
,5
]}

Matias-Garcia, Pamela R. ^{[6
,7
,8
]}

Wuttke, Matthias ^{[4
,5
,9
]}

Coassin, Stefan ^{[10
]}

Thio, Chris H. L. ^{[11
]}

Kleber, Marcus E. ^{[12
]}

Winkler, Thomas W. ^{[1
,2
]}

Wanner, Veronika ^{[1
,2
]}

Chai, Jin-Fang ^{[13
,14
]}

Chu, Audrey Y. ^{[15
]}

Cocca, Massimiliano ^{[16
]}

Feitosa, Mary F. ^{[17
]}

Ghasemi, Sahar ^{[18
,19
]}

Hoppmann, Anselm ^{[4
,5
]}

Horn, Katrin ^{[20
,21
]}

Li, Man ^{[22
]}

Nutile, Teresa ^{[23
]}

Scholz, Markus ^{[20
,21
]}

Sieber, Karsten B. ^{[24
]}

Teumer, Alexander ^{[18
,19
]}

Tin, Adrienne ^{[25
,26
]}

Wang, Judy ^{[17
]}

Tayo, Bamidele O. ^{[27
]}

Ahluwalia, Tarunveer S. ^{[28
]}

Almgren, Peter ^{[29
]}

Bakker, Stephan J. L. ^{[30
]}

Banas, Bernhard ^{[3
]}

Bansal, Nisha ^{[31
,32
]}

Biggs, Mary L. ^{[33
,34
]}

Boerwinkle, Eric ^{[35
]}

Bottinger, Erwin P. ^{[36
,37
,38
]}

Brenner, Hermann ^{[39
,40
]}

Carroll, Robert J. ^{[41
]}

Chalmers, John ^{[42
,43
,44
]}

Chee, Miao-Li ^{[45
]}

Chee, Miao-Ling ^{[45
]}

Cheng, Ching-Yu ^{[14
,45
,46
,47
]}

Coresh, Josef ^{[44
]}

de Borst, Martin H. ^{[30
]}

Degenhardt, Frauke ^{[48
]}

Eckardt, Kai-Uwe ^{[49
,50
]}

Endlich, Karlhans ^{[19
,51
]}

Franke, Andre ^{[48
]}

Freitag-Wolf, Sandra ^{[52
]}

Gampawar, Piyush ^{[53
]}

Gansevoort, Ron T. ^{[30
]}

Ghanbari, Mohsen ^{[54
,55
]}

Gieger, Christian ^{[6
,7
,56
]}

机构：

[1] Univ Regensburg, Dept Genet Epidemiol, Franz Josef Strauss Allee 11, D-93053 Regensburg, Germany

[2] Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany

[3] Univ Hosp Regensburg, Dept Nephrol, Freiburg, Germany

[4] Univ Freiburg, Fac Med, Dept Biometry Epidemiol & Med Bioinformat, Inst Genet Epidemiol, Freiburg, Germany

[5] Univ Freiburg, Med Ctr, Freiburg, Germany

[6] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany

[7] Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany

[8] Tech Univ Munich, TUM Sch Med, Munich, Germany

[9] Univ Freiburg, Fac Med, Dept Med 4, Renal Div, Freiburg, Germany

[10] Med Univ Innsbruck, Inst Genet Epidemiol, Dept Genet & Pharmacol, Innsbruck, Austria

[11] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[12] Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, Mannheim, Germany

[13] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore

[14] Natl Univ Hlth Syst, Singapore, Singapore

[15] Merck & Co Inc, Genet, Kenilworth, NJ USA

[16] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy

[17] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[18] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[19] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany

[20] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[21] Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany

[22] Univ Utah, Dept Med, Div Nephrol & Hypertens, Salt Lake City, UT 84112 USA

[23] CNR, Inst Genet & Biophys Adriano Buzzati Traverso, Naples, Italy

[24] GlaxoSmithKline, Human Genet, Collegeville, PA USA

[25] Univ Mississippi, Med Ctr, Memory Impairment & Neurodegenerat Dementia MIND, Jackson, MS 39216 USA

[26] Univ Mississippi, Med Ctr, Dept Med, Div Nephrol, Jackson, MS 39216 USA

[27] Loyola Univ Chicago, Dept Publ Hlth Sci, Maywood, IL USA

[28] Steno Diabet Ctr Copenhagen, Gentofte, Denmark

[29] Lund Univ, Dept Clin Sci Malmo, Diabet & Cardiovasc Dis Genet Epidemiol, Malmo, Sweden

[30] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, Groningen, Netherlands

[31] Univ Washington, Div Nephrol, Seattle, WA 98195 USA

[32] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA

[33] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[34] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[35] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA

[36] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[37] Hasso Plattner Inst, Digital Hlth Ctr, Potsdam, Germany

[38] Univ Potsdam, Potsdam, Germany

[39] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[40] Heidelberg Univ, Network Aging Res, Heidelberg, Germany

[41] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA

[42] Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia

[43] Univ Oxford, George Inst Global Hlth, Oxford, England

[44] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[45] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore

[46] Duke NUS Med Sch, Acad Clin Program Eye ACP, Ophthalmol & Visual Sci, Singapore, Singapore

[47] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore

[48] Christian AlbrechtsUniv Kiel, Inst Clin Mol Biol, Kiel, Germany

[49] Charite Univ Med Berlin, Dept Nephrol & Med Intens Care, Berlin, Germany

[50] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Nephrol & Hypertens, Erlangen, Germany

来源：

KIDNEY INTERNATIONAL | 2021年 / 99卷 / 04期

关键词：

acute kidney injury; end-stage kidney disease; genome-wide association study; rapid eGFRcrea decline; GLOMERULAR-FILTRATION-RATE; ASSOCIATION; DISEASE; TYPE-2; MORTALITY; LOCI; ALBUMINURIA; PROGRESSION; CKD;

D O I：

10.1016/j.kint.2020.09.030

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

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.

引用

页码：926 / 939

页数：14

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