Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

  1. Marcus G. Pezzolesi1,
  2. G. David Poznik1,
  3. Josyf C. Mychaleckyj2,
  4. Andrew D. Paterson3,4,
  5. Michelle T. Barati5,
  6. Jon B. Klein5,
  7. Daniel P.K. Ng1,6,
  8. Grzegorz Placha1,7,
  9. Luis H. Canani1,8,
  10. Jacek Bochenski1,
  11. Daryl Waggott9,
  12. Michael L. Merchant5,
  13. Bozena Krolewski1,
  14. Lucia Mirea4,9,
  15. Krzysztof Wanic1,
  16. Pisut Katavetin1,
  17. Masahiko Kure1,
  18. Pawel Wolkow1,10,
  19. Jonathon S. Dunn1,
  20. Adam Smiles1,
  21. William H. Walker1,
  22. Andrew P. Boright11,
  23. Shelley B. Bull4,9,
  24. the DCCT/EDIC Research Group*,
  25. Alessandro Doria1,
  26. John J. Rogus1,
  27. Stephen S. Rich2,
  28. James H. Warram1 and
  29. Andrzej S. Krolewski1
  1. 1Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts;
  2. 2Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia;
  3. 3Program in Genetics and Genome Biology, Hospital for Sick Children, University of Toronto, Toronto, Canada;
  4. 4Dalla Lana School of Public Health, University of Toronto, Toronto, Canada;
  5. 5Kidney Disease Program, University of Louisville, Louisville, Kentucky;
  6. 6Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;
  7. 7Department of Hypertension, Medical University of Warsaw, Warsaw, Poland;
  8. 8Department of Endocrinology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil;
  9. 9Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada;
  10. 10Department of Pharmacology, Jagiellonian University, School of Medicine, Krakow, Poland;
  11. 11Department of Medicine, University Health Network, University of Toronto, Toronto, Canada.
  1. 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.

| Table of Contents

This Article

  1. Diabetes vol. 58 no. 6 1403-1410
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db08-1514v1
    2. 58/6/1403 most recent