The rs1800629 polymorphism of the TNFα gene in type 2 diabetes mellitus: association with nephropathy

Main Article Content

S.V. Ziablytsev
O.P. Chernobrytsev
D.S. Ziablytsev

Abstract

Background. In diabetes mellitus (DM), endothelial dysfunction (EDF) is formed that determines the rate and severity of the disease complications. Among other factors, there is the presence of genetic polymorphism, which can be different in different ethnic populations. The purpose was to determine the relationship between rs1800629 polymorphism of the TNFα gene and type 2 DM in Ukrainian patients, as well as the association with the development of complications and EDF factors. Materials and methods. The study involved data from 152 Ukrainian patients with type 2 DM aged 34–80 years (53.9 ± 8.4 years) and 95 apparently healthy persons (controls). According to the results of clinical and laboratory examinations, the presence of retinopathy, nephropathy was determined by levels of microalbuminuria and glomerular filtration rate, sensory polyneuropathy, angiopathy of the lower extremities, and hypertension. The rs1800629 polymorphism was determined by real time polymerase chain reaction (Gene Amp® PCR System 7500 Applied Biosystems, USA) using the TaqMan Mutation Detection Assays Life­Technology (USA) test systems. Statistical data processing was performed by Statistica 10 (StatSoft Inc., USA). Results. The distribution of alleles (χ2 = 5.91; p = 0.015), but not genotypes (χ2 = 5.65; p = 0.059) rs1800629 of the TNFα gene was associated with the disease development in the Ukrainian cohort of patients with type 2 DM. Minor allele A increased the risk of type 2 DM (odds ratio = 1.71; 95% confidence interval 1.11–2.65). The presence of allele A led to the reduction of glomerular filtration rate that explained the association of rs1800629 with nephropathy (χ2 = 6.38; p = 0.041) and was due to the development of EDF with high levels of TNFα (p < 0.001), endothelin­1 (p = 0.026) and nitric oxide (p < 0.001). Conclusions. The rs1800629 polymorphism of the TNFα gene was associated with the type 2 DM in patients from the Ukrainian population, and among the complications — with the development of nephropathy in terms of the glomerular filtration rate, which was related to the presence of minor allele A and more severe EDF in such patients as compared to G allele carriers.

Article Details

How to Cite
Ziablytsev, S., O. Chernobrytsev, and D. Ziablytsev. “The rs1800629 Polymorphism of the TNFα Gene in Type 2 Diabetes Mellitus: Association With Nephropathy”. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), vol. 15, no. 1, Apr. 2019, pp. 16-22, doi:10.22141/2224-0721.15.1.2019.158687.
Section
Original Researches

References

Pankiv VI. Diabetes mellitus: diagnostic criteria, etiology and pathogenesis. Mìžnarodnij endokrinologìčnij žurnal. 2013;(56):53-64. doi: 10.22141/2224-0721.8.56.2013.84796. (in Ukrainian).

Leontis LM, Hess-Fischl A. Type 2 Diabetes Complications: How to Prevent Short- and Long-term Complications. Available from: https://www.endocrineweb.com/conditions/type-2-diabetes/type-2-diabetes-complications. Accessed: September 27, 2018.

Pi X, Xie L, Patterson C. Emerging roles of vascular endothelium in metabolic homeostasis. Circ Res. 2018 Aug 3;123(4):477-494. doi: 10.1161/CIRCRESAHA.118.313237.

Siniachenko OV, Ziablitsev SV, Chernobryvtsev PA. Endotelial'naia disfunktsiia pri glomerulonefrite [Endothelial dysfunction in glomerulonephritis]. Donetsk: New World; 2006. 152 p. (in Russian).

Carrizzo A, Izzo C, Oliveti M, et al. The main determinants of diabetes mellitus vascular complications: endothelial dysfunction and platelet hyperaggregation. Int J Mol Sci. 2018 Sep 28;19(10). pii: E2968. doi: 10.3390/ijms19102968.

Liu ZH, Ding YL, Xiu LC, et al. A meta-analysis of the association between TNF-α -308G>A polymorphism and type 2 diabetes mellitus in Han Chinese population. PLoS One. 2013;8(3):e59421. doi: 10.1371/journal.pone.0059421.

Nadeem A, Mumtaz S, Naveed AK, Mansoor Q, Aslam M, Ismail M. Association of ADIPOQ C-11377G (rs266729), TNF-α G-308A (rs1800629) and TNF-α G-238A (rs361525) single nucleotide polymorphisms with type 2 diabetes mellitus in Pakistani population. J Coll Physicians Surg Pak. 2017;27(10):625-630. doi: 2722.

Kaidonis G, Craig JE, Gillies MC, et al. Promoter polymorphism at the tumour necrosis factor/lymphotoxin-alpha locus is associated with type of diabetes but not with susceptibility to sight-threatening diabetic retinopathy. Diab Vasc Dis Res. 2016;13(2):164-167. doi: 10.1177/1479164115616902.

Tavares NA, Santos MM, Moura R, et al. Association of TNF-α, CTLA4, and PTPN22 polymorphisms with type 1 diabetes and other autoimmune diseases in Brazil. Genet Mol Res. 2015 Dec 28;14(4):18936-44. doi: 10.4238/2015.December.28.42.

Sesti LF, Crispim D, Canani LH, et al. The -308G>A polymorphism of the TNF gene is associated with proliferative diabetic retinopathy in Caucasian Brazilians with type 2 diabetes. Invest Ophthalmol Vis Sci. 2015 Jan 29;56(2):1184-90. doi: 10.1167/iovs.14-15758.

Mogilevskyy SIu, Bushuieva OV, Ziablitsev S V, Natrus LV. Relationship of the AKR1B1 rs759853 and rs9640883 with the development of diabetic retinopathy. Journal of Ophthalmology (Ukraine). 2017;(2):3-7. doi: 31288/oftalmolzh2017237.

Dhamodharan U, Viswanathan V, Krishnamoorthy E, Rajaram R, Aravindhan V. Genetic association of IL-6, TNF-α and SDF-1 polymorphisms with serum cytokine levels in diabetic foot ulcer. Gene. 2015 Jul 1;565(1):62-67. doi: 10.1016/j.gene.2015.03.063.

Doody NE, Dowejko MM, Akam EC, et al. The role of TLR4, TNF-α and IL-1β in type 2 diabetes mellitus development within a North Indian population. Ann Hum Genet. 2017 Jul;81(4):141-146. doi: 10.1111/ahg.12197.

Jamil K, Jayaraman A, Ahmad J, Joshi S, Yerra SK. TNF-alpha -308G/A and -238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus. Saudi J Biol Sci. 2017 Sep;24(6):1195-1203. doi: 10.1016/j.sjbs.2016.05.012.

Luna GI, da Silva IC, Sanchez MN. Association between -308G/A TNFA Polymorphism and Susceptibility to Type 2 Diabetes Mellitus: A Systematic Review. J Diabetes Res. 2016;2016:6309484. doi: 10.1155/2016/6309484.

International Diabetes federation (IDF). IDF Diabetes Atlas 8th Ed, 2017. Available from: http://diabetesatlas.org/resources/2017-atlas.html.

Ministry of Нealth of Ukraine. Order on December 21, 2012 № 1118. On Adoption and Implementation of Medical and Technological Documents on the Standardization of Medical Care for Type 2 Diabetes Mellitus. Available from: https://zakon.rada.gov.ua/rada/show/v1118282-12?lang=uk. Accessed: December 21, 2012. (in Ukrainian).

Zhao Y, Li Z, Zhang L, et al. The TNF-alpha -308G/A polymorphism is associated with type 2 diabetes mellitus: an updated meta-analysis. Mol Biol Rep. 2014 Jan;41(1):73-83. doi: 10.1007/s11033-013-2839-1.

Hameed I, Masoodi SR, Malik PA, Mir SA, Ghazanfar K, Ganai BA. Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression. Gene. 2018 Jun 30;661:51-59. doi: 10.1016/j.gene.2018.03.095.

Umapathy D, Krishnamoorthy E, Mariappanadar V, Viswanathan V, Ramkumar KM. Increased levels of circulating (TNF-α) is associated with (-308G/A) promoter polymorphism of TNF-α gene in Diabetic Nephropathy. Int J Biol Macromol. 2018 Feb;107(Pt B):2113-2121. doi: 10.1016/j.ijbiomac.2017.10.078.

Keri KC, Samji NS, Blumenthal S. Diabetic nephropathy: newer therapeutic perspectives. J Community Hosp Intern Med Perspect. 2018 Aug 23;8(4):200-207. doi: 10.1080/20009666.2018.1500423.