Multiple SOD1/SFRS15 variants are associated with the development and progression of diabetic nephropathy: The DCCT/EDIC Genetics study
- Hussam Al-Kateb1,
- Andrew P. Boright3,
- Lucia Mirea2,,4,
- Xinlei Xie2,
- Rinku Sutradhar2,,12,
- Ali Mowjoodi1,
- Bhupinder Bharaj1,
- Michelle Liu1,
- Jean M. Bucksa5,
- Valerie L. Arends5,
- Michael W. Steffes5,
- Patricia A. Cleary6,
- Wanjie Sun6,
- John M. Lachin6,
- Paul S. Thorner7,,8,
- Michael Ho7,
- Amy Jayne McKnight9,
- A. Peter Maxwell9,
- David A. Savage9,
- Kenneth K. Kidd10,
- Judith R. Kidd10,
- William C. Speed10,
- Trevor J. Orchard11,
- Rachel G. Miller11,
- Lei Sun1,,4,
- Shelley B. Bull2,,4,
- Andrew D. Paterson (andrew.paterson{at}utoronto.ca)1,,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, Canada.
- 2 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada.
- 3 Department of Medicine, University Health Network, University of Toronto, Toronto, Canada.
- 4 Department of Public Health Sciences, University of Toronto, Toronto, Canada.
- 5 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.
- 6 The Biostatistics Center, The George Washington University, Rockville, MD 20852.
- 7 Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada.
- 8 Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
- 9 Nephrology Research Group, Queen's University of Belfast, Belfast, Northern Ireland, UK.
- 10 Department of Genetics, Yale University School of Medicine, New Haven, CT.
- 11 University of Pittsburgh, Pittsburgh, PA.
- 12 Institute for Clinical Evaluative Sciences, Toronto, Canada.
Abstract
Background: Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes (T1D), few gene variants have been consistently associated with these outcomes.
Methods: We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands with T1D 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 (HR=1.82, 95%CI=1.29-2.57, p=6.4 × 10−4, q=0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, rs204732 which were also associated (p<10−3) with persistent microalbuminuria, while 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, nor 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
-
- Received July 31, 2007.
- Accepted September 30, 2007.
- Copyright © American Diabetes Association
