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.
BACKGROUND
Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, 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 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.
Al-Kateb
Hussam
H
Program in Genetics and Genome Biology, The Hospital for Sick Children, TMDT Building East Tower, Rm. 15-707, 101 College St., Toronto, Ontario, Canada.
Boright
Andrew P
AP
Mirea
Lucia
L
Xie
Xinlei
X
Sutradhar
Rinku
R
Mowjoodi
Alireza
A
Bharaj
Bhupinder
B
Liu
Michelle
M
Bucksa
Jean M
JM
Arends
Valerie L
VL
Steffes
Michael W
MW
Cleary
Patricia A
PA
Sun
Wanjie
W
Lachin
John M
JM
Thorner
Paul S
PS
Ho
Michael
M
McKnight
Amy Jayne
AJ
Maxwell
A Peter
AP
Savage
David A
DA
Kidd
Kenneth K
KK
Kidd
Judith R
JR
Speed
William C
WC
Orchard
Trevor J
TJ
Miller
Rachel G
RG
Sun
Lei
L
Bull
Shelley B
SB
Paterson
Andrew D
AD
D000409:Alanine; D000419:Albuminuria / Q000235:genetics; D019943:Amino Acid Substitution; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics; D018450:Disease Progression; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics*; D012694:Serine; D000068103:Serine-Arginine Splicing Factors; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome
D007004:Hypoglycemic Agents; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C000606290:SOD1 protein, human; D000068103:Serine-Arginine Splicing Factors; D012694:Serine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine