Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.
OBJECTIVE
Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection.


METHODS
We genotyped approximately 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications.


RESULTS
A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney.


CONCLUSIONS
We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.
Pezzolesi
Marcus G
MG
Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Poznik
G David
GD
Mychaleckyj
Josyf C
JC
Paterson
Andrew D
AD
Barati
Michelle T
MT
Klein
Jon B
JB
Ng
Daniel P K
DP
Placha
Grzegorz
G
Canani
Luis H
LH
Bochenski
Jacek
J
Waggott
Daryl
D
Merchant
Michael L
ML
Krolewski
Bozena
B
Mirea
Lucia
L
Wanic
Krzysztof
K
Katavetin
Pisut
P
Kure
Masahiko
M
Wolkow
Pawel
P
Dunn
Jonathon S
JS
Smiles
Adam
A
Walker
William H
WH
Boright
Andrew P
AP
Bull
Shelley B
SB
Doria
Alessandro
A
Rogus
John J
JJ
Rich
Stephen S
SS
Warram
James H
JH
Krolewski
Andrzej S
AS
D002874:Chromosome Mapping; D003598:Cytoskeletal Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011507:Proteinuria / Q000235:genetics; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D000099149:Ezrin; C071058:moesin; C071776:radixin