Genome-wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes Mellitus
- Marcus G. Pezzolesi1,
- G. David Poznik1,
- Josyf C. Mychaleckyj2,
- Andrew D. Paterson3,4,
- Michelle T. Barati5,
- Jon B. Klein5,
- Daniel P.K. Ng1,6,
- Grzegorz Placha1,7,
- Luis H. Canani1,8,
- Jacek Bochenski1,
- Daryl Waggott9,
- Michael L. Merchant5,
- Bozena Krolewski1,
- Lucia Mirea4,9,
- Krzysztof Wanic1,
- Pisut Katavetin1,
- Masahiko Kure1,
- Pawel Wolkow1,10,
- Jonathon S. Dunn1,
- Adam Smiles1,
- William H. Walker1,
- Andrew P. Boright11,
- Shelley B. Bull4,9,
- DCCT/EDIC Research Group12,
- Alessandro Doria1,
- John J. Rogus1,
- Stephen S. Rich2,
- James H. Warram1 and
- Andrzej S. Krolewski (Andrzej.Krolewski{at}joslin.harvard.edu)1
- 1Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215
- 2Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908
- 3Program in Genetics and Genome Biology, Hospital for Sick Children, University of Toronto, Toronto, Canada M5G 1L7
- 4Dalla Lana School of Public Health, University of Toronto, Toronto, Canada M5T 3M7
- 5Kidney Disease Program, University of Louisville, Louisville, KY 40202
- 6Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine,National University of Singapore, Singapore 117597
- 7Department of Hypertension, Medical University of Warsaw, Warsaw, Poland 02-097
- 8Department of Endocrinology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil 90035-903
- 9Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada M5T 3L9
- 10Department of Pharmacology, Jagiellonian University, School of Medicine, Krakow, Poland 31-531
- 1111Department of Medicine, University Health Network, University of Toronto, Toronto, Canada M5G 2C4
- 1212Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (see N Engl J Med 353:2643-53, 2005)
Abstract
Objective: Despite extensive evidence for genetic susceptibility to diabetic nephropathy (DN), the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to DN, 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 cases (284 with proteinuria and 536 with ESRD) and 885 controls with type 1 diabetes (T1D). Confirmation of implicated SNPs was sought in 1,304 participants of the DCCT/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 DN with P <1×10−5. The strongest association was at the FRMD3 (FERM domain containing 3) locus (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 DN were supported in the DCCT/EDIC study (HR=1.33, P=0.02 and HR=1.32, P=0.01, respectively). We demonstrated expression of both FRMD3 and CARS in human kidney.
Conclusions: We identified genetic associations for susceptibility to DN 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 T1D.
Footnotes
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- Received October 31, 2008.
- Accepted February 23, 2009.
- Copyright © American Diabetes Association
