Multiple Superoxide Dismutase 1/Splicing Factor Serine Alanine 15 Variants Are Associated With the Development and Progression of Diabetic Nephropathy

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics Study

  1. Hussam Al-Kateb1,
  2. Andrew P. Boright2,
  3. Lucia Mirea34,
  4. Xinlei Xie3,
  5. Rinku Sutradhar35,
  6. Alireza Mowjoodi1,
  7. Bhupinder Bharaj1,
  8. Michelle Liu1,
  9. Jean M. Bucksa6,
  10. Valerie L. Arends6,
  11. Michael W. Steffes6,
  12. Patricia A. Cleary7,
  13. Wanjie Sun7,
  14. John M. Lachin7,
  15. Paul S. Thorner89,
  16. Michael Ho8,
  17. Amy Jayne McKnight10,
  18. A. Peter Maxwell10,
  19. David A. Savage10,
  20. Kenneth K. Kidd11,
  21. Judith R. Kidd11,
  22. William C. Speed11,
  23. Trevor J. Orchard12,
  24. Rachel G. Miller12,
  25. Lei Sun14,
  26. Shelley B. Bull34,
  27. Andrew D. Paterson14 and
  28. the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group*
  1. 1Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
  3. 3Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Ontario, Canada
  4. 4Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
  5. 5Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
  6. 6Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
  7. 7The Biostatistics Center, The George Washington University, Rockville, Maryland
  8. 8Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada
  9. 9Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  10. 10Nephrology Research Group, Queen's University of Belfast, Belfast, Northern Ireland, U.K
  11. 11Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
  12. 12University of Pittsburgh, Pittsburgh, Pennsylvania
  1. Address correspondence and reprint requests to Dr. Andrew Paterson, Program in Genetics and Genome Biology, The Hospital for Sick Children, TMDT Building East Tower, Rm. 15-707, 101 College St., Toronto, Ontario, Canada M5G 1L7. E-mail: andrew.paterson{at}utoronto.ca

Abstract

BACKGROUND— Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently associated with these outcomes.

RESEARCH DESIGN AND METHODS— We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using multivariate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery rate q values were calculated separately for each outcome.

RESULTS— We observed association between rs17880135 in the 3′ region of superoxide dismutase 1 (SOD1) and the incidence of both severe nephropathy (hazard ratio [HR] 2.62 [95% CI 1.64–4.18], P = 5.6 × 10−5, q = 0.06) and persistent microalbuminuria (1.82 [1.29–2.57], P = 6.4 × 10−4, q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which were also associated (P < 10−3) with persistent microalbuminuria, whereas rs17880135 and rs17881180 were similarly associated with the development of severe nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results. We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression in lymphoblastoid cell lines.

CONCLUSIONS— Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC study.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on October 2007. DOI: 10.2337/db07-1059. DCCT clinical trial reg. no. NCT00360815, EDIC clinical trial reg. no. NCT00360893, clinicaltrials.gov.

  • H.A.-K. and A.P.B. contributed equally to this work, and L.M. and X.X. contributed equally to this work.

  • *

    * A complete list of investigators and members of the research group appears in N Engl J Med 353:2643–2653, 2005.

  • 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.

    • Accepted September 30, 2007.
    • Received July 31, 2007.
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  1. Diabetes vol. 57 no. 1 218-228
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