Multiple loci associated with indices of renal function and chronic kidney disease.
Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.
Anna
A
Köttgen
Nicole L
NL
Glazer
Abbas
A
Dehghan
Shih-Jen
SJ
Hwang
Ronit
R
Katz
Man
M
Li
Qiong
Q
Yang
Vilmundur
V
Gudnason
Lenore J
LJ
Launer
Tamara B
TB
Harris
Albert V
AV
Smith
Dan E
DE
Arking
Brad C
BC
Astor
Eric
E
Boerwinkle
Georg B
GB
Ehret
Ingo
I
Ruczinski
Robert B
RB
Scharpf
Yii-Der Ida
YD
Chen
Ian H
IH
de Boer
Talin
T
Haritunians
Thomas
T
Lumley
Mark
M
Sarnak
David
D
Siscovick
Emelia J
EJ
Benjamin
Daniel
D
Levy
Ashish
A
Upadhyay
Yurii S
YS
Aulchenko
Albert
A
Hofman
Fernando
F
Rivadeneira
André G
AG
Uitterlinden
Cornelia M
CM
van Duijn
Daniel I
DI
Chasman
Guillaume
G
Paré
Paul M
PM
Ridker
W H Linda
WH
Kao
Jacqueline C
JC
Witteman
Josef
J
Coresh
Michael G
MG
Shlipak
Caroline S
CS
Fox
D002874:Chromosome Mapping; D015331:Cohort Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000502:physiology* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D015201:Meta-Analysis as Topic; D009088:Mucoproteins / Q000235:genetics*; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D058949:Uromodulin
D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin