title: Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.
abstract: 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.
authors.affiliation: Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Marcus G
authors.initials: MG
authors.lastname: Pezzolesi
authors.forename: G David
authors.initials: GD
authors.lastname: Poznik
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Barati
authors.forename: Jon B
authors.initials: JB
authors.lastname: Klein
authors.forename: Daniel P K
authors.initials: DP
authors.lastname: Ng
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Placha
authors.forename: Luis H
authors.initials: LH
authors.lastname: Canani
authors.forename: Jacek
authors.initials: J
authors.lastname: Bochenski
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.forename: Michael L
authors.initials: ML
authors.lastname: Merchant
authors.forename: Bozena
authors.initials: B
authors.lastname: Krolewski
authors.forename: Lucia
authors.initials: L
authors.lastname: Mirea
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wanic
authors.forename: Pisut
authors.initials: P
authors.lastname: Katavetin
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kure
authors.forename: Pawel
authors.initials: P
authors.lastname: Wolkow
authors.forename: Jonathon S
authors.initials: JS
authors.lastname: Dunn
authors.forename: Adam
authors.initials: A
authors.lastname: Smiles
authors.forename: William H
authors.initials: WH
authors.lastname: Walker
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Boright
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Bull
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: John J
authors.initials: JJ
authors.lastname: Rogus
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: 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
chemical_list: D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D000099149:Ezrin; C071058:moesin; C071776:radixin