Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, with multiple genetic and environmental factors involving in its etiology. ACE and eNOS gene were considered to have important roles in the development and progression of DN. In this study, a case–control study was carried out to investigate the effects of 7 SNPs in ACE gene and 2 SNPs in eNOS gene in the development of DN in Northern China.7 SNPs including A240T, A2350G, A5466C, A2215G, T3892C, C1237T and C3409T of ACE gene and 2 SNPs (G894T and T786C) of eNOS gene were genotyped by polymerase chain reaction restriction fragment length polymorphism method. 431 type 2 diabetic patients with nephropathy (cases) were compared to 420 type 2 diabetic patients without nephropathy (controls) in the study. Data were analyzed by SPSS 17.0 and HaploView software. The frequency distribution of A2350G, 4 haplotyps in ACE gene and G894T in eNOS gene were demonstrated to be different between case and control groups significantly. Whereas other SNPs and haplotypes had no differences in two cohorts. The results revealed that variations of ACE and eNOS gene had association with DN, which indicated ACE and eNOS gene may play an important role in pathogenesis of DN in Northern Chinese Han population.
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Ahluwalia TS, Ahuja M, Rai TS et al (2008) Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians. Mol Cell Biochem 314(1–2):9–17
Wang F, Fang Q, Yu N et al (2012) Association between genetic polymorphism of the angiotensin-converting enzyme and diabetic nephropathy: a meta-analysis comprising 26,580 subjects. J Renin Angiotensin Aldosterone Syst 13(1):161–174
Ahluwalia TS, Ahuja M, Rai TS et al (2009) ACE variants interact with the RAS pathway to confer risk and protection against type 2 diabetic nephropathy. DNA Cell Biol 28(3):141–150
El-Din Bessa SS, Hamdy SM (2011) Impact of nitric oxide synthase Glu298Asp polymorphism on the development of end-stage renal disease in type 2 diabetic Egyptian patients. Ren Fail 33(9):878–884
Seaquist ER, Goetz FC, Rich S, Barbosa J (1989) Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320(18):1161–1165
Agius E, Attard G, Shakespeare L et al (2006) Familial factors in diabetic nephropathy: an offspring study. Diabet Med 23(3):331–334
Schmidt S, Ritz E (1997) Genetics of the renin-angiotensin system and renal disease: a progress report. Curr Opin Nephrol Hypertens 6(2):146–151
Purnamasari D, Widjojo BD, Antono D, Syampurnawati M (2012) ACE gene polymorphism and atherosclerotic lesion of carotid artery among offsprings of type 2 diabetes mellitus. Acta Med Indones 44(2):128–134
Lely AT, Luik PT, Navis G (2007) Angiotensin I-converting enzyme: a pathogenetic role in diabetic renal damage? Curr Diabetes Rev 3(1):41–52
Gong AM, Li XY, Wang YQ et al (2012) Association study of ACE polymorphisms and systemic lupus erythematosus in Northern Chinese Han population. Mol Biol Rep 39(10):9485–9491
Burns KD (2000) Angiotensin II and its receptors in the diabetic kidney. Am J Kidney Dis 36(3):449–467
Kim S, Iwao H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52(1):11–34
Li X, An J, Guo R et al (2010) Association of the genetic polymorphisms of the ACE gene and the eNOS gene with lupus nephropathy in northern Chinese population. BMC Med Genet 11:94
Al-Harbi EM, Farid EM, Gumaa KA, Masuadi EM, Singh J (2011) Angiotensin-converting enzyme gene polymorphisms and T2DM in a case-control association study of the Bahraini population. Mol Cell Biochem 350(1–2):119–125
Prabhakar SS (2004) Role of nitric oxide in diabetic nephropathy. Semin Nephrol 24(4):333–344
Prabhakar SS (2005) Pathogenic role of nitric oxide alterations in diabetic nephropathy. Curr Diab Rep 5(6):449–454
Bellini MH, Figueira MN, Piccoli MF et al (2007) Association of endothelial nitric oxide synthase gene intron 4 polymorphism with end-stage renal disease. Nephrology (Carlton) 12(3):289–293
He Y, Fan Z, Zhang J et al (2011) Polymorphisms of eNOS gene are associated with diabetic nephropathy: a meta-analysis. Mutagenesis 26(2):339–349
Akcay A, Sezer S, Ozdemir FN et al (2004) Association of the genetic polymorphisms of the renin-angiotensin system and endothelial nitric oxide synthase with chronic renal transplant dysfunction. Transplantation 78(6):892–898
Bazzaz JT, Amoli MM, Pravica V et al (2010) eNOS gene polymorphism association with retinopathy in type 1 diabetes. Ophthalmic Genet 31(3):103–107
Rupert JL, Kidd KK, Norman LE, Monsalve MV, Hochachka PW, Devine DV (2003) Genetic polymorphisms in the Renin-Angiotensin system in high-altitude and low-altitude Native American populations. Ann Hum Genet 67(Pt 1):17–25
Koehle MS, Wang P, Guenette JA, Rupert JL (2006) No association between variants in the ACE and angiotensin II receptor 1 genes and acute mountain sickness in Nepalese pilgrims to the Janai Purnima Festival at 4380 m. High Alt Med Biol 7(4):281–289
Zhu X, Bouzekri N, Southam L et al (2001) Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet 68(5):1139–1148
Qi Y, Niu W, Zhu T, Zhou W, Qiu C (2008) Synergistic effect of the genetic polymorphisms of the renin-angiotensin-aldosterone system on high-altitude pulmonary edema: a study from Qinghai-Tibet altitude. Eur J Epidemiol 23(2):143–152
Hwang SJ, Tsai JC, Chen HC (2010) Epidemiology, impact and preventive care of chronic kidney disease in Taiwan. Nephrology (Carlton) 15(Suppl 2):3–9
Harrison-Bernard LM (2009) The renal renin-angiotensin system. Adv Physiol Educ 33(4):270–274
Erdos EG (1976) Conversion of angiotensin I to angiotensin II. Am J Med 60(6):749–759
Currie D, McKnight AJ, Patterson CC, Sadlier DM, Maxwell AP (2010) Investigation of ACE, ACE2 and AGTR1 genes for association with nephropathy in Type 1 diabetes mellitus. Diabet Med 27(10):1188–1194
Kennon B, Petrie JR, Small M, Connell JM (1999) Angiotensin-converting enzyme gene and diabetes mellitus. Diabet Med 16(6):448–458
Kaufman KM, Kelly J, Gray-McGuire C et al (2001) Linkage analysis of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and systemic lupus erythematosus. Mol Cell Endocrinol 177(1–2):81–85
Nawaz SK, Hasnain S (2011) Association of ACE ID and ACE G2350A polymorphism with increased blood pressure in persons exposed to different sound levels in Pakistan. Int Arch Occup Environ Health 84(4):355–360
Saeed M, Khan AN, Siddiqui S, Saboohi K, Ali SO, Frossard PM (2004) Association of ACE gene haplotype with essential hypertension. J Hum Hypertens 18(12):913–914
Alvi FM, Hasnain S (2009) ACE I/D and G2350A polymorphisms in Pakistani hypertensive population of Punjab. Clin Exp Hypertens 31(5):471–480
Su SL, Lu KC, Lin YF et al (2012) Gene polymorphisms of angiotensin-converting enzyme and angiotensin II type 1 receptor among chronic kidney disease patients in a Chinese population. J Renin Angiotensin Aldosterone Syst 13(1):148–154
McKenzie CA, Abecasis GR, Keavney B et al (2001) Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE). Hum Mol Genet 10(10):1077–1084
Abdollahi MR, Huang S, Rodriguez S et al (2008) Homogeneous assay of rs4343, an ACE I/D proxy, and an analysis in the British Women’s Heart and Health Study (BWHHS). Dis Markers 24(1):11–17
Rahimi Z, Vaisi-Raygani A, Parsian A (2012) Concomitant presence of endothelial nitric oxide 894T and angiotensin II-converting enzyme D alleles are associated with diabetic nephropathy in a Kurdish population from Western Iran. Nephrology (Carlton) 17(2):175–181
Shin Shin Y, Baek SH, Chang KY et al (2004) Relations between eNOS Glu298Asp polymorphism and progression of diabetic nephropathy. Diabetes Res Clin Pract 65(3):257–265
Mollsten A, Lajer M, Jorsal A, Tarnow L (2009) The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes. Mol Genet Metab 97(1):80–84
Noiri E, Satoh H, Taguchi J et al (2002) Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension 40(4):535–540
Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS (2000) Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int 57(2):405–413
Heesom AE, Hibberd ML, Millward A, Demaine AG (1997) Polymorphism in the 5′-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes. Diabetes 46(2):287–291
Shultz PJ, Schorer AE, Raij L (1990) Effects of endothelium-derived relaxing factor and nitric oxide on rat mesangial cells. Am J Physiol 258(1 Pt 2):F162–F167
Acknowledgments
We sincerely acknowledge the numerous donors for making this work possible. We thank the corresponding people of General Hospital of Shenyang Military Area Command, Changzheng Hospital of Second Military Medical University, who helped us selflessly during the process of the study. We are also grateful to the sample donors for the study.
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Huo, P., Zhang, D., Guan, X. et al. Association between genetic polymorphisms of ACE & eNOS and diabetic nephropathy. Mol Biol Rep 42, 27–33 (2015). https://doi.org/10.1007/s11033-014-3736-y
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DOI: https://doi.org/10.1007/s11033-014-3736-y