Genome-wide association study of kidney function decline in individuals of European descent

被引：107

作者：

Gorski, Mathias ^{[1
,2
]}

Tin, Adrienne ^{[3
]}

Garnaas, Maija ^{[4
]}

McMahon, Gearoid M. ^{[5
,6
,7
]}

Chu, Audrey Y. ^{[8
]}

Tayo, Bamidele O. ^{[9
]}

Pattaro, Cristian ^{[10
]}

Teumer, Alexander ^{[11
]}

Chasman, Daniel I. ^{[8
]}

Chalmers, John ^{[12
]}

Hamet, Pavel ^{[13
]}

Tremblay, Johanne ^{[14
]}

Woodward, Marc ^{[12
]}

Aspelund, Thor ^{[15
,16
]}

Eiriksdottir, Gudny ^{[15
]}

Gudnason, Vilmundur ^{[15
,16
]}

Harris, Tamara B. ^{[17
]}

Launer, Lenore J. ^{[17
]}

Smith, Albert V. ^{[15
,16
]}

Mitchell, Braxton D. ^{[18
,19
,20
]}

O'Connell, Jeffrey R. ^{[18
,19
]}

Shuldiner, Alan R. ^{[18
,19
,20
]}

Coresh, Josef ^{[3
,21
]}

Li, Man ^{[3
]}

Freudenberger, Paul ^{[22
]}

Hofer, Edith ^{[23
]}

Schmidt, Helena ^{[22
]}

Schmidt, Reinhold ^{[24
]}

Holliday, Elizabeth G. ^{[25
]}

Mitchell, Paul ^{[26
]}

Wang, Jie Jin ^{[26
]}

de Boer, Ian H. ^{[27
]}

Li, Guo ^{[28
]}

Siscovick, David S. ^{[28
,29
]}

Kutalik, Zoltan ^{[30
,31
]}

Corre, Tanguy ^{[30
]}

Vollenweider, Peter ^{[32
]}

Waeber, Gerard ^{[32
]}

Gupta, Jayanta ^{[33
]}

Kanetsky, Peter A. ^{[33
]}

Hwang, Shih-Jen ^{[7
]}

Olden, Matthias ^{[1
,7
]}

Yang, Qiong ^{[7
,34
]}

de Andrade, Mariza ^{[35
]}

Atkinson, Elizabeth J. ^{[35
]}

Kardia, Sharon L. R. ^{[36
]}

Turner, Stephen T. ^{[35
]}

Stafford, Jeanette M. ^{[37
]}

Ding, Jingzhong ^{[38
]}

Liu, Yongmei ^{[39
]}

机构：

[1] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany

[2] Univ Hosp Regensburg, Dept Nephrol, D-93042 Regensburg, Germany

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

[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Boston, MA USA

[7] NHLBI, Framingham Heart Study, Framingham, MA USA

[8] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[9] Loyola Univ Chicago, Loyola Med Ctr, Dept Publ Hlth Serv, Maywood, IL USA

[10] Univ Lubeck, European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy

[11] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany

[12] Univ Sydney, George Inst Global Hlth, Sydney, NSW 2006, Australia

[13] Univ Montreal, Ctr Hosp, Ctr Rech, Montreal, PQ, Canada

[14] CHUM Res Center, Montreal, PQ, Canada

[15] Icelandic Heart Assoc, Res Inst, Kopavogur, Iceland

[16] Univ Iceland, Reykjavik, Iceland

[17] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[18] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[19] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA

[20] Univ Maryland, Sch Med, Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA

[21] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA

[22] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[23] Med Univ Graz, Inst Med Informat Stat & Documentat, Dept Neurol, Graz, Austria

[24] Med Univ Graz, Dept Neurol, Graz, Austria

[25] Univ Newcastle, CReDITSS, HMRI, Ctr Clin Epidemiol & Biostat, Callaghan, NSW 2308, Australia

[26] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Vis Res, Sydney, NSW 2006, Australia

[27] Univ Washington, Seattle, WA 98195 USA

[28] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[29] New York Acad Med, New York, NY USA

[30] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland

[31] Swiss Inst Bioinformat, Dept Med Genet, Lausanne, Switzerland

[32] Univ Lausanne Hosp, Dept Internal Med, Lausanne, Switzerland

[33] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA

[34] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[35] Mayo Clin, Rochester, MN USA

[36] Univ Michigan, Ann Arbor, MI 48109 USA

[37] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA

[38] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA

[39] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA

[40] Univ Milan, Dept Hlth Sci, Milan, Italy

[41] San Paolo Hosp, Div Nephrol, Milan, Italy

[42] Maastricht Univ, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands

[43] Univ Leuven, Dept Cardiovasc Sci, Div Hypertens & Cardiovasc Rehabil, Studies Coordinating Ctr, Leuven, Belgium

[44] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany

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

[46] German Ctr Diabet Res, Neuherberg, Germany

[47] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany

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

[49] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[50] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany

来源：

KIDNEY INTERNATIONAL | 2015年 / 87卷 / 05期

基金：

美国国家卫生研究院;

关键词：

chronic kidney disease; genome-wide association study; kidney function decline; kidney development; population genetics; single nucleotide polymorphism; zebrafish; GLOMERULAR-FILTRATION-RATE; RENAL-FUNCTION; DEAFNESS DFNB12; MOUSE MODEL; GENE; DISEASE; MORTALITY; RISK; PROGRESSION; MUTATIONS;

D O I：

10.1038/ki.2014.361

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：

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

引用

页码：1017 / 1029

页数：13

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