We investigated the association of polymorphisms of three genes implicated in oxidative stress: CYBA C242T, RAGE −374T/A and −429T/C, and ALOX12 Arg261Gln, with the delay of microalbuminuria onset in patients with type 1 diabetes mellitus (DT1).
A total of 162 T1D patients presenting with diabetes for 32.9 ± 9 years were included in the study; 53 had persistent microalbuminuria (>30 mg/l) and 109 did not. Onset of diabetes, microalbuminuria and end-stage renal disease (ESRD) were recorded as bio-clinical data. We determined polymorphism association of microalbuminuria with a Cox regression model.
All polymorphisms respected the Hardy–Weinberg equilibrium. The Cox regression model validated four significant variables associated with microalbuminuria: RAGE 374AA (HR 4.19 [1.84–9.58] (p = 0.001)), CYBA TT+TC (HR 2.1 [1.16–3.80], p = 0.015), male sex (HR 1.92 [1.07–3.43], p = 0.028) and diabetes diagnosis at the pediatric stage (HR 1.85 [1.03–3.32], p = 0.039). The same association was found with ESRD (p = 0.028 and p = 0.033 for CYBA TC+TT and RAGE 374AA, respectively). CYBA C242T and RAGE 374T/A were not significantly associated with diabetic retinopathy.
CYBA C242T and RAGE −374T/A correlate with microalbuminuria onset in the French DT1 cohort. The same correlation with ESRD onset supports the argument for the involvement of a genetic predisposition involving kidney-specific oxidative stress for diabetic nephropathy.
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Rosolowsky ET, Skupien J, Smiles AM et al (2011) Risk for ESRD in Type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol 22:545–553. doi:10.1681/ASN.2010040354
Ritz E, Rychlík I, Locatelli F, Halimi S (1999) End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis Off J Natl Kidney Found 34:795–808. doi:10.1016/S0272-6386(99)70035-1
D’Addio F, Trevisani A, Ben Nasr M et al (2014) Harnessing the immunological properties of stem cells as a therapeutic option for diabetic nephropathy. Acta Diabetol 51:897–904. doi:10.1007/s00592-014-0603-1
Doria A, Niewczas MA, Fiorina P (2012) Can existing drugs approved for other indications retard renal function decline in patients with type 1 diabetes and nephropathy? Semin Nephrol 32:437–444. doi:10.1016/j.semnephrol.2012.07.006
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820. doi:10.1038/414813a
Thallas-Bonke V, Thorpe SR, Coughlan MT et al (2008) Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway. Diabetes 57:460–469. doi:10.2337/db07-1119
Ha H, Hwang I-A, Park JH, Lee HB (2008) Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract 82(Suppl 1):S42–S45. doi:10.1016/j.diabres.2008.09.017
Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313. doi:10.1152/physrev.00044.2005
Babelova A, Avaniadi D, Jung O et al (2012) Role of Nox4 in murine models of kidney disease. Free Radic Biol Med 53:842–853. doi:10.1016/j.freeradbiomed.2012.06.027
Hodgkinson AD, Millward BA, Demaine AG (2003) Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with type 1 diabetes. Diabetes Care 26:3111–3115
Fang S, Wang L, Jia C (2010) Association of p22phox gene C242T polymorphism with coronary artery disease: a meta-analysis. Thromb Res 125:e197–e201. doi:10.1016/j.thromres.2010.01.001
Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S (2012) Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury. Pharmacol Res Off J Ital Pharmacol Soc 65:297–302. doi:10.1016/j.phrs.2011.11.001
Wendt TM, Tanji N, Guo J et al (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:1123–1137. doi:10.1016/S0002-9440(10)63909-0
Franko B, Brault J, Jouve T et al (2014) Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2014.08.042
Hudson BI, Stickland MH, Futers TS, Grant PJ (2001) Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. Diabetes 50:1505–1511
Matsunaga-Irie S, Maruyama T, Yamamoto Y et al (2004) Relation between development of nephropathy and the p22phox C242T and receptor for advanced glycation end product G1704T gene polymorphisms in type 2 diabetic patients. Diabetes Care 27:303–307
Santos KG, Canani LH, Gross JL et al (2005) Relationship of p22phox C242T polymorphism with nephropathy in type 2 diabetic patients. J Nephrol 18:733–738
Gu L, Su L, Liang B et al (2013) Association between the C242T polymorphism of p22phox gene and ischemic stroke: a meta-analysis. J Neurol Sci 330:100–110. doi:10.1016/j.jns.2013.04.022
Lim SC, Goh SK, Lai YR et al (2006) Relationship between common functional polymorphisms of the p22phox gene (−930A>G and +242C>T) and nephropathy as a result of Type 2 diabetes in a Chinese population. Diabet Med J Br Diabet Assoc 23:1037–1041. doi:10.1111/j.1464-5491.2006.01916.x
Li A, Prasad A, Mincemoyer R et al (1999) Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function. Am J Med Genet 86:57–61. doi:10.1002/(SICI)1096-8628(19990903)86:1<57:AID-AJMG11>3.0.CO;2-R
Liu Y, Freedman BI, Burdon KP et al (2008) Association of arachidonate 12-lipoxygenase genotype variation and glycemic control with albuminuria in type 2 diabetes. Am J Kidney Dis Off J Natl Kidney Found 52:242–250. doi:10.1053/j.ajkd.2007.12.033
Shimo-Nakanishi Y, Hasebe T, Suzuki A et al (2004) Functional effects of NAD(P)H oxidase p22(phox) C242T mutation in human leukocytes and association with thrombotic cerebral infarction. Atherosclerosis 175:109–115. doi:10.1016/j.atherosclerosis.2004.01.043
Zhu Y, Marchal CC, Casbon A-J et al (2006) Deletion mutagenesis of p22phox subunit of flavocytochrome b558: identification of regions critical for gp91phox maturation and NADPH oxidase activity. J Biol Chem 281:30336–30346. doi:10.1074/jbc.M607191200
Xu M, Chen X, Yan L et al (2008) Association between (AC)n dinucleotide repeat polymorphism at the 5′-end of the aldose reductase gene and diabetic nephropathy: a meta-analysis. J Mol Endocrinol 40:243–251. doi:10.1677/JME-07-0152
Li Y, Wang S (2010) Glycated albumin activates NADPH oxidase in rat mesangial cells through up-regulation of p47phox. Biochem Biophys Res Commun 397:5–11. doi:10.1016/j.bbrc.2010.04.084
Quintana LF, Guzmán B, Collado S et al (2006) A coding polymorphism in the 12-lipoxygenase gene is associated to essential hypertension and urinary 12(S)-HETE. Kidney Int 69:526–530. doi:10.1038/sj.ki.5000147
Krolewski AS, Gohda T, Niewczas MA (2014) Progressive renal decline as the major feature of diabetic nephropathy in type 1 diabetes. Clin Exp Nephrol. doi:10.1007/s10157-013-0900-y
Perkins BA, Krolewski AS (2005) Early nephropathy in type 1 diabetes: a new perspective on who will and who will not progress. Curr Diab Rep 5:455–463
Secrest AM, Becker DJ, Kelsey SF et al (2010) All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry. Diabetes Care 33:2573–2579. doi:10.2337/dc10-1170
Bedard K, Attar H, Bonnefont J et al (2009) Three common polymorphisms in the CYBA gene form a haplotype associated with decreased ROS generation. Hum Mutat 30:1123–1133. doi:10.1002/humu.21029
The authors thank Michelle Mollin for technical assistance. We are grateful to the University Joseph Fourier, the Faculty of Medicine, the Regional Clinical Research Department, DRCI and the Grenoble University Hospital.
Conflict of interest
The authors declare that they have no conflict of interest.
All participants gave written consent before inclusion. The study was approved by the ethical committee (CPP Sud-Est V, Grenoble, France) and recorded in clinicaltrial.gov (NCT01371955).
Human and animal rights
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
Informed consent was obtained from all patients for being included in the study.
Marie José Stasia and Philippe Zaoui have contributed equally to this work.
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Franko, B., Benhamou, PY., Genty, C. et al. RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up. Acta Diabetol 53, 469–475 (2016). https://doi.org/10.1007/s00592-015-0820-2
- Diabetic nephropathy
- Type 1 diabetes
- Genetic polymorphisms