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-Kateb, Andrew P. Boright, Lucia Mirea, Xinlei Xie, Rinku Sutradhar, Alireza Mowjoodi, Bhupinder Bharaj, Michelle Liu, Jean M. Bucksa, Valerie L. Arends, Michael W Steffes, Patricia A. Cleary, Wanjie Sun, John M. Lachin, Paul S. Thorner, Michael Ho, Amy Jayne McKnight, A. Peter Maxwell, David A. Savage, Kenneth K. Kidd & 7 others Judith R. Kidd, William C. Speed, Trevor J. Orchard, Rachel G. Miller, Lei Sun, Shelley B. Bull, Andrew D. Paterson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)218-228
Number of pages11
JournalDiabetes
Volume57
Issue number1
DOIs
StatePublished - Jan 1 2008

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Genetic Engineering
Diabetic Nephropathies
Diabetes Complications
Alanine
Serine
Epidemiology
Type 1 Diabetes Mellitus
Kidney
Genetic Association Studies
Serum
Proportional Hazards Models
Genes
Single Nucleotide Polymorphism
Cluster Analysis
Case-Control Studies
Research Design
Genotype
RNA Splicing Factors
Superoxide Dismutase-1
Cell Line

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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. / Al-Kateb, Hussam; Boright, Andrew P.; Mirea, Lucia; Xie, Xinlei; Sutradhar, Rinku; Mowjoodi, Alireza; Bharaj, Bhupinder; Liu, Michelle; Bucksa, Jean M.; Arends, Valerie L.; Steffes, Michael W; Cleary, Patricia A.; Sun, Wanjie; Lachin, John M.; Thorner, Paul S.; Ho, Michael; McKnight, Amy Jayne; Maxwell, A. Peter; Savage, David A.; Kidd, Kenneth K.; Kidd, Judith R.; Speed, William C.; Orchard, Trevor J.; Miller, Rachel G.; Sun, Lei; Bull, Shelley B.; Paterson, Andrew D.

In: Diabetes, Vol. 57, No. 1, 01.01.2008, p. 218-228.

Research output: Contribution to journalArticle

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 & Paterson, AD 2008, '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', Diabetes, vol. 57, no. 1, pp. 218-228. https://doi.org/10.2337/db07-1059
Al-Kateb, Hussam ; Boright, Andrew P. ; Mirea, Lucia ; Xie, Xinlei ; Sutradhar, Rinku ; Mowjoodi, Alireza ; Bharaj, Bhupinder ; Liu, Michelle ; Bucksa, Jean M. ; Arends, Valerie L. ; Steffes, Michael W ; Cleary, Patricia A. ; Sun, Wanjie ; Lachin, John M. ; Thorner, Paul S. ; Ho, Michael ; McKnight, Amy Jayne ; Maxwell, A. Peter ; Savage, David A. ; Kidd, Kenneth K. ; Kidd, Judith R. ; Speed, William C. ; Orchard, Trevor J. ; Miller, Rachel G. ; Sun, Lei ; Bull, Shelley B. ; Paterson, Andrew D. / 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. In: Diabetes. 2008 ; Vol. 57, No. 1. pp. 218-228.
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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.",
author = "Hussam Al-Kateb and Boright, {Andrew P.} and Lucia Mirea and Xinlei Xie and Rinku Sutradhar and Alireza Mowjoodi and Bhupinder Bharaj and Michelle Liu and Bucksa, {Jean M.} and Arends, {Valerie L.} and Steffes, {Michael W} and Cleary, {Patricia A.} and Wanjie Sun and Lachin, {John M.} and Thorner, {Paul S.} and Michael Ho and McKnight, {Amy Jayne} and Maxwell, {A. Peter} and Savage, {David A.} and Kidd, {Kenneth K.} and Kidd, {Judith R.} and Speed, {William C.} and Orchard, {Trevor J.} and Miller, {Rachel G.} and Lei Sun and Bull, {Shelley B.} and Paterson, {Andrew D.}",
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T1 - Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy

T2 - The diabetes control and complications trial/epidemiology of diabetes interventions and complications genetics study

AU - Al-Kateb, Hussam

AU - Boright, Andrew P.

AU - Mirea, Lucia

AU - Xie, Xinlei

AU - Sutradhar, Rinku

AU - Mowjoodi, Alireza

AU - Bharaj, Bhupinder

AU - Liu, Michelle

AU - Bucksa, Jean M.

AU - Arends, Valerie L.

AU - Steffes, Michael W

AU - Cleary, Patricia A.

AU - Sun, Wanjie

AU - Lachin, John M.

AU - Thorner, Paul S.

AU - Ho, Michael

AU - McKnight, Amy Jayne

AU - Maxwell, A. Peter

AU - Savage, David A.

AU - Kidd, Kenneth K.

AU - Kidd, Judith R.

AU - Speed, William C.

AU - Orchard, Trevor J.

AU - Miller, Rachel G.

AU - Sun, Lei

AU - Bull, Shelley B.

AU - Paterson, Andrew D.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

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