1. 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.
- Author
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Al-Kateb H, Boright AP, Mirea L, Xie X, Sutradhar R, Mowjoodi A, Bharaj B, Liu M, Bucksa JM, Arends VL, Steffes MW, Cleary PA, Sun W, Lachin JM, Thorner PS, Ho M, McKnight AJ, Maxwell AP, Savage DA, Kidd KK, Kidd JR, Speed WC, Orchard TJ, Miller RG, Sun L, Bull SB, and Paterson AD
- Subjects
- Alanine, Albuminuria genetics, Amino Acid Substitution, Diabetic Nephropathies drug therapy, Diabetic Nephropathies enzymology, Diabetic Retinopathy genetics, Disease Progression, Genotype, Humans, Hypoglycemic Agents therapeutic use, Polymorphism, Single Nucleotide, Serine, Serine-Arginine Splicing Factors, Superoxide Dismutase-1, Treatment Outcome, Diabetic Nephropathies genetics, Genetic Variation, Nuclear Proteins genetics, RNA-Binding Proteins genetics, Superoxide Dismutase genetics
- 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 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.
- Published
- 2008
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