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Published online October 3, 2007
Diabetes 57:218-228, 2008
DOI: 10.2337/db07-1059
© 2008 by the American Diabetes Association
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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

Hussam Al-Kateb1, Andrew P. Boright2, Lucia Mirea3,4, Xinlei Xie3, Rinku Sutradhar3,5, Alireza Mowjoodi1, Bhupinder Bharaj1, Michelle Liu1, Jean M. Bucksa6, Valerie L. Arends6, Michael W. Steffes6, Patricia A. Cleary7, Wanjie Sun7, John M. Lachin7, Paul S. Thorner8,9, Michael Ho8, Amy Jayne McKnight10, A. Peter Maxwell10, David A. Savage10, Kenneth K. Kidd11, Judith R. Kidd11, William C. Speed11, Trevor J. Orchard12, Rachel G. Miller12, Lei Sun1,4, Shelley B. Bull3,4, Andrew D. Paterson1,4, and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group*

1 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
2 Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
3 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Ontario, Canada
4 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
5 Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
6 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
7 The Biostatistics Center, The George Washington University, Rockville, Maryland
8 Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada
9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
10 Nephrology Research Group, Queen's University of Belfast, Belfast, Northern Ireland, U.K
11 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
12 University of Pittsburgh, Pittsburgh, Pennsylvania

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

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 x 10–5, q = 0.06) and persistent microalbuminuria (1.82 [1.29–2.57], P = 6.4 x 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.


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