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Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes Marcus G. Pezzolesi 1 , G. David Poznik 1 , Josyf C. Mychaleckyj 2 , Andrew D. Paterson 3 , 4 , Michelle T. Barati 5 , Jon B. Klein 5 , Daniel P.K. Ng 1 , 6 , Grzegorz Placha 1 , 7 , Luis H. Canani 1 , 8 , Jacek Bochenski 1 , Daryl Waggott 9 , Michael L. Merchant 5 , Bozena Krolewski 1 , Lucia Mirea 4 , 9 , Krzysztof Wanic 1 , Pisut Katavetin 1 , Masahiko Kure 1 , Pawel Wolkow 1 , 10 , Jonathon S. Dunn 1 , Adam Smiles 1 , William H. Walker 1 , Andrew P. Boright 11 , Shelley B. Bull 4 , 9 , the DCCT/EDIC Research Group * , Alessandro Doria 1 , John J. Rogus 1 , Stephen S. Rich 2 , James H. Warram 1 and Andrzej S. Krolewski 1 1 Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts; 2 Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia; 3 Program in Genetics and Genome Biology, Hospital for Sick Children, University of Toronto, Toronto, Canada; 4 Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; 5 Kidney Disease Program, University of Louisville, Louisville, Kentucky; 6 Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 7 Department of Hypertension, Medical University of Warsaw, Warsaw, Poland; 8 Department of Endocrinology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; 9 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada; 10 Department of Pharmacology, Jagiellonian University, School of Medicine, Krakow, Poland; 11 Department of Medicine, University Health Network, University of Toronto, Toronto, Canada. Corresponding author: Andrzej S. Krolewski, andrzej.krolewski{at}joslin.harvard.edu . 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. RESEARCH DESIGN AND METHODS We genotyped ∼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 × 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 × 10 −7 ). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 × 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. Footnotes *Study group members for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group are listed in N Engl J Med 2005;353:2643–2653. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 31, 2008. Accepted February 23, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.