Haplotype Analysis of RAGE Gene Polymorphisms and Association with Increased Risk of Diabetic Nephropathy

Document Type : Original Article

Authors

1 Student Research Committee, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

2 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

3 Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran

4 Cellular and Molecular Research Center, Research Institute for prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran

5 Midland Memorial Hospital 400 Rosalind Redfern Grover Pkwy, Midland, TX 79701, USA

6 Cellular and Molecular Research Center, Research Institute for prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran & Department of Biochemistry and Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

Abstract

Background: The present study aimed at evaluating the association between the -429T/C and -374T/A polymorphisms of RAGE (Receptor for Advanced Glycation End Products) gene promoter and diabetic nephropathy as well as examining its possible application as candidate markers of diabetic nephropathy among the population of Qazvin, Iran.
Methods: In this study, the diabetic patients were divided into the two groups of with or without nephropathy. The frequency of genotype and allele were determined using TETRA-Primer ARMS-PCR. Hardy-Weinberg equilibrium test and correlation of polymorphisms, odds ratio (OR), and FAMHAP software were used for haplotype analysis.
Results: Based on our data, the CC genotype of -429T/C polymorphism may play a protective role against the development of nephropathy (OR=0.586, 95%; CI: 0.158-2.167) while, the AA genotype may be associated with increased risk of the disease (OR=1.889, 95%; CI: 0.454-7.854). Allele’s analysis revealed that the C allele of -429T/C polymorphism maybe protective against the appearance of nephropathy (OR=0.794, 95%; CI: 0.48-1.314) whereas, the A allele may be related to increased risk for nephropathy (OR=1.452, 95%; CI: 0.783-2.695). Haplotype analysis demonstrated that there was no significant correlation between the two -429T/C and -374T/A SNPs (χ2=5.125, p value=0.135). However, it was found that the CA haplotype may have a protective effect against the development of nephropathy (OR=0.48, 95%; CI: 0.14-1.64) while, the TA haplotype may increase the risk of the disease (OR=2.06, 95%; CI:1.01-4.23).
Conclusion: Overall, no correlation between the -374T/A and -429T/C polymorphisms and the haplotypes in RAGE gene and the occurrence of diabetic nephropathy, was established.

Keywords


  1. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Progression of diabetic nephropathy. Kidney Int. 2001; 59(2):702-9. doi: 10.1046/j.1523-1755.2001.059002702.x.
  2. Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, et al. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes. 2009; 58(6):1403-10.
  3. Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, et al. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000; 11(9):1656-1666. doi: 10.1681/ASN.V1191656.
  4. Oesterle A, Bowman MA. S100A12 and the S100/Calgranulins: Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets. Arterioscler Thromb Vasc Biol. 2015; 35(12):2496-507. doi: 10.1161/ATVBAHA.115.302072.
  5. Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, et al. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell Mol Life Sci. 2002; 59(7):1117-28. doi: 10.1007/s00018-002-8491-x.
  6. Pickering RJ, Tikellis C, Rosado CJ, Tsorotes D, Dimitropoulos A, Smith M, et al. Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis. J Clin Invest. 2019; 129(1):406-21. doi: 1172/jci99987.
  7. Chen YJ, Chan DC, Chiang CK, Wang CC, Yang TH, Lan KC, et al. Advanced glycation end-products induced VEGF production and inflammatory responses in human synoviocytes via RAGE-NF-κB pathway activation. J Orthop Res. 2016; 34(5):791-800. doi: 10.1002/jor.23083.
  8. Moridi H, Karimi J, Sheikh N, Goodarzi MT, Saidijam M, Yadegarazari R, et al. Resveratrol-Dependent Down-regulation of Receptor for Advanced Glycation End-products and Oxidative Stress in Kidney of Rats with Diabetes. Int J Endocrinol Metab. 2015; 13(2):e23542. doi: 10.5812/ijem.23542.
  9. Hudson BI, Stickland MH, Futers TS, Grant PJ. Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. Diabetes. 2001; 50(6):1505-11. doi: 10.2337/diabetes.50.6.1505.
  10. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014; 37:81-90. doi: 10.2337/dc14-S081.
  11. Pugliese G. Updating the natural history of diabetic nephropathy. Acta Diabetol. 2014; 51(6):905-15. doi: 10.1007/s00592-014-0650-7.
  12. Satirapoj B, Adler SG. Prevalence and Management of Diabetic Nephropathy in Western Countries. Kidney Dis (Basel). 2015; 1(1):61-70. doi: 10.1159/000382028.
  13. Antonaros F, Olivucci G, Cicchini E, Ramacieri G, Pelleri MC, Vitale L, et al. MTHFR C677T polymorphism analysis: A simple, effective restriction enzyme-based method improving previous protocols. Mol Genet Genomic Med. 2019; 7(5):e628. doi: 10.1002/mgg3.628.
  14. Song X, Li J, Fei P, Zhang X, Pan C, Chen H, et al. Polymorphisms within the BouleGene Detected by Tetra-Primer Amplification Refractory Mutation System PCR (T-ARMS-PCR) are Significantly Associated with Goat Litter Size. Animals (Basel). 2019; 9(11):910. doi: 10.3390/ani9110910.
  15. Ng ZX, Kuppusamy UR, Poh R, Tajunisah I, Koay AC, Fong KC, et al. Lack of association between Gly82Ser, 1704G/T and 2184A/G of RAGE gene polymorphisms and retinopathy susceptibility in Malaysian diabetic patients. Genet Mol Res. 2012; 11(1):455-61. doi: 10.4238/2012.
  16. Xie L, Deng Y, Yuan Y, Tan X, Liu L, Li N, et al. Association of SNP rs1867277 in FOXE1 Gene and Cleft Lip with or without Cleft Palate in a Han Chinese Population. Fetal Pediatr Pathol. 2018; 37(2):89-94. doi: 10.1080/15513815.2018.1424278.
  17. Kassaee S M, Taghi Goodarzi M, Abbasi Oshaghi E. Antioxidant, Antiglycation and Anti-Hyperlipidemic Effects of Trigonella foenumand Cinnamon in Type 2 Diabetic Rats, Jundishapur J Nat Pharm Prod. 2018; 13(1):e38414. doi: 10.8512/jjnpp.38414.
  18. Myint KM, Yamamoto Y, Doi T, Kato I, Harashima A, Yonekura H, et al RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin. Diabetes. 2006; 55(9):2510-22. doi: 10.2337/db06-0221.
  19. Reiniger N, Lau K, McCalla D, Eby B, Cheng B, Lu Y, et al. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes. 2010; 59(8):2043-54. doi: 10.2337/db09-1766.
  20. Wang H, Li Y, Yu W, Ma L, Ji X, Xiao W. Expression of the receptor for advanced glycation end-products and frequency of polymorphism in lung cancer. Oncol Lett. 2015; 10(1):51-60. doi: 10.3892/ol.2015.3200.
  21. Wong FN, Chua KH, Kuppusamy UR, Wong CM, Lim SK, Tan JA. Association of the receptor for advanced glycation end-products (RAGE) gene polymorphisms in Malaysian patients with chronic kidney disease. PeerJ. 2016; 4:e1908. doi: 10.7717/peerj.1908.
  22. Heidary SS, Bathaie SZ, Bahmani F, Moshtaghi-Kashanian G. Assessment of Oral Glycine and Lysine Therapy on Receptor for Advanced Glycation End Products and Transforming Growth Factor Beta Expression in the Kidney of Streptozotocin-Induced Diabetic Rats in Comparison with Normal Rats. Journal of Kerman University of Medical Sciences. 2014; 21(6):454-468. [In Persian]
  23. Wfdt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol. 2003; 162(4):1123-1137. doi:10.1016/S0002-9440(10)63909-0.
  24. Martens HA, Nienhuis HL, Gross S, van der Steege G, Brouwer E, Berden JH, et al. Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis. Lupus. 2012; 21(9):959-68. doi: 10.1177/0961203312444495.
  25. Serveaux-Dancer M, Jabaudon M, Creveaux I, Belville C, Blondonnet R, Gross C, et al. Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism. Dis Markers. 2019; 2019:2067353. doi: 10.1155/2019/2067353.
  26. Chellappa RC, Rani P. G82S RAGE polymorphism is associated with Alzheimer's disease. Front Biosci (Elite Ed). 2020; 12:150-161. doi: 10.2741/E864.
  27. Tripathi AK, Chawla D, Bansal S, Banerjee BD, Madhu SV, Kalra OP. Association of RAGE gene polymorphism with vascular complications in Indian type 2 diabetes mellitus patients. Diabetes Res Clin Pract. 2014; 103(3):474-481. doi: 10.1016/j.diabres. 2013.12.004.
  28. Prasad P, Tiwari AK, Kumar KP, Ammini AC, Gupta A, Gupta R, et al. Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes. BMC Med Genet. 2010; 11:25. doi: 10.1186/1471-2350-11-52
  29. Shi Z, Lu W, Xie G. Association between the RAGE gene -374T/A, -429T/C polymorphisms and diabetic nephropathy: a meta-analysis. Ren Fail. 2015; 37:751-756.
  30. Lindholm E, Bakhtadze E, Sjögren M, Cilio CM, Agardh E, Groop L, et al. The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients. Diabetologia. 2006; 49(11):2745-55. doi: 10.1007/s00125-006-0412-3. 
  31. Baragetti I, Norata GD, Sarcina C, Baragetti A, Rastelli F, Buzzi L, et al. -374 T/A RAGE polymorphism is associated with chronic kidney disease progression in subjects affected by nephrocardiovascular disease. PLoS One. 2013; 8(4):e60089. doi: 10.1371/journal.pone.0060089.
  32. Pettersson-Fernholm K, Forsblom C, Hudson BI, Perola M, Grant PJ, Groop PH, et al. The functional -374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular disease in type 1 diabetic patients. Diabetes. 2003; 52(3):891-4. doi: 10.2337/diabetes.52.3.891. 
  33. dos Santos KG, Canani LH, Gross JL, Tschiedel B, Pires Souto KE, Roisenberg I. The -374A allele of the receptor for advanced glycation end products gene is associated with a decreased risk of ischemic heart disease in African-Brazilians with type 2 diabetes. Mol Genet Metab. 2005; 85(2):149-56. doi: 10.1016/j.ymgme.2005.02.010. 
  34. Chen C, Wang C, Hu C, Han Y, Zhao L, Zhu X, et al. Normoalbuminuric diabetic kidney disease. Front Med. 2017 Sep;11(3):310-318. doi: 10.1007/s11684-017-0542-7.
  35. Li A, Yi B, Liu Y, Wang J, Dai Q, Huang Y, Li YC, Zhang H. Urinary NGAL and RBP Are Biomarkers of Normoalbuminuric Renal Insufficiency in Type 2 Diabetes Mellitus. J Immunol Res. 2019; 2019:5063089. doi: 10.1155/2019/5063089.
  36. Hauser E, Cremer N, Hein R, Deshmukh H. Haplotype-based analysis: a summary of GAW16 Group 4 analysis. Genet Epidemiol. 2009; 33(1):24-8. doi: 10.1002/gepi.20468. 
  37. JiXiong X, BiLin X, MingGong Y, ShuQin L. -429T/C and -374T/A polymorphisms of RAGE gene promoter are not associated with diabetic retinopathy in Chinese patients with type 2 diabetes. Diabetes Care 2003; 26(9):2696-2697. doi: 10.2337/diacare.26.9.2696.
  38. Kankova K, Stejskalova A, Hertlova M, Znojil V. Haplotype analysis of the RAGE gene: identification of a haplotype marker for diabetic nephropathy in type 2 diabetes mellitus. Nephrol Dial Transplant. 2005; 20(6):1093-102. doi: 10.1093/ndt/gfh711.
  39. Zee RY, Romero JR, Gould JL, Ricupero DA, Ridker PM. Polymorphisms in the advanced glycosylation end product-specific receptor gene and risk of incident myocardial infarction or ischemic stroke. Stroke. 2006; 37(7):1686-90. doi: 10.1161/01.STR.0000226994.
    6c.
  40. Peng WH, Lu L, Wang LJ, Yan XX, Chen QJ, Zhang Q, et al. RAGE gene polymorphisms are associated with circulating levels of endogenous secretory RAGE but not with coronary artery disease in Chinese patients with type 2 diabetes mellitus. Arch Med Res. 2009; 40(5):393-8. doi: 10.1016/j.arcmed.2009.06. 008.
  41. Kalousova M, Jachymová M, Mestek O, Hodkova M, Kazderová M, Tesar V, et al. Receptor for advanced glycation end products--soluble form and gene polymorphisms in chronic haemodialysis patients. Nephrol Dial Transplant. 2007; 22(7):2020-6. doi: 10.1093/ndt/gfm050.