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03-01-2024 | Diabetic Nephropathy | Original Article

Cytokine gene polymorphism with type 2 diabetes and diabetic nephropathy in population from West India

Authors: Brijesh K. Dabhi, Kinnari N. Mistry, Jinal M. Thakor, Sishir Gang

Published in: International Journal of Diabetes in Developing Countries | Issue 4/2024

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Abstract

Objective

Genetic polymorphisms of the angiogenesis, inflammatory cascade, or apoptosis genes can influence chronic complications in diabetic patients. Cytokine gene polymorphisms are considered vital in diabetes and diabetic nephropathy (DN) susceptibility. The present study evaluated the role of cytokine gene polymorphism in type 2 diabetes and diabetic nephropathy.

Methods

A total number of 648 participants comprising 180 healthy individuals, 164 type 2 diabetes mellitus patients without any complications, 148 individuals with diabetic nephropathy, and 156 with non-diabetic nephropathy were included in this study. The IL-6 (-634 C/G), IL-18  (-607 A/C), IL-4 (-590C/T), and IL-10 (-592 C/A) polymorphism were analyzed using the PCR-RFLP method, and their expression analysis was done using real-time PCR

Results

We found a significant difference in the genotype frequency of IL-6 and IL-10 in the diabetic nephropathy group compared to the control, whereas no significant difference was found in IL-18 and IL-4.

Conclusion

The IL-6 -634C/G and IL-10-592 C/A polymorphisms were found to be associated with diabetic nephropathy in the West Indian population. The higher transcript level of inflammatory cytokines in patient groups compared to the control group may suggest the essential role of inflammation in the pathogenesis of diabetes and diabetic nephropathy.
Literature
1.
go back to reference Lim A. Diabetic nephropathy - complications and treatment. Int J Nephrol Renov Dis. 2014;7:361–81.CrossRef Lim A. Diabetic nephropathy - complications and treatment. Int J Nephrol Renov Dis. 2014;7:361–81.CrossRef
3.
go back to reference Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DS. Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int. 2007;72:549–56.CrossRefPubMed Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DS. Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int. 2007;72:549–56.CrossRefPubMed
5.
go back to reference Mocan MC, Kadayifcilar S, Eldem B. Elevated intravitreal interleukin-6 levels in patients with proliferative diabetic retinopathy. Can J Ophthalmol. 2006;41:747–52.CrossRefPubMed Mocan MC, Kadayifcilar S, Eldem B. Elevated intravitreal interleukin-6 levels in patients with proliferative diabetic retinopathy. Can J Ophthalmol. 2006;41:747–52.CrossRefPubMed
6.
go back to reference Williams MD, Nadler JL. Inflammatory mechanisms of diabetic complications. Curr Diab Rep. 2007;7:242–8.CrossRefPubMed Williams MD, Nadler JL. Inflammatory mechanisms of diabetic complications. Curr Diab Rep. 2007;7:242–8.CrossRefPubMed
7.
go back to reference Reed J, Bain S, Kanamarlapudi V. A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives. Diabetes Metab Syndrome Obes Targets Ther. 2021;14:3567–602.CrossRef Reed J, Bain S, Kanamarlapudi V. A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives. Diabetes Metab Syndrome Obes Targets Ther. 2021;14:3567–602.CrossRef
8.
go back to reference Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412–9.CrossRefPubMedPubMedCentral Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412–9.CrossRefPubMedPubMedCentral
9.
go back to reference Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, Itoshima T, Makino H. Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Care. 2005;28:2890–5.CrossRefPubMed Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, Itoshima T, Makino H. Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Care. 2005;28:2890–5.CrossRefPubMed
10.
go back to reference Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001;112:146–52.CrossRefPubMed Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001;112:146–52.CrossRefPubMed
11.
go back to reference Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM. Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Front Immunol. 2014;5(253):1–6. Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM. Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Front Immunol. 2014;5(253):1–6.
12.
go back to reference Helminen M, Nuolivirta K, Virta M, Halkosalo A, Korppi M, Vesikari T, Hurme M. IL-10 gene polymorphism at -1082 A/G is associated with severe rhinovirus bronchiolitis in infants. Pediatr Pulmonol. 2008;43:391–5.CrossRefPubMed Helminen M, Nuolivirta K, Virta M, Halkosalo A, Korppi M, Vesikari T, Hurme M. IL-10 gene polymorphism at -1082 A/G is associated with severe rhinovirus bronchiolitis in infants. Pediatr Pulmonol. 2008;43:391–5.CrossRefPubMed
14.
go back to reference Samadi Shams S, Zununi Vahed S, Soltanzad F, Kafil V, Barzegari A, Atashpaz S, Barar J. Highly effective DNA extraction method from fresh, frozen, dried and clotted blood samples. Bioimpacts. 2011;1:183–7.PubMedPubMedCentral Samadi Shams S, Zununi Vahed S, Soltanzad F, Kafil V, Barzegari A, Atashpaz S, Barar J. Highly effective DNA extraction method from fresh, frozen, dried and clotted blood samples. Bioimpacts. 2011;1:183–7.PubMedPubMedCentral
15.
go back to reference Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today. 2000;21:60–4.CrossRefPubMed Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today. 2000;21:60–4.CrossRefPubMed
16.
go back to reference Kitamura A, Hasegawa G, Obayashi H, Kamiuchi K, Ishii M, Yano M, Yoshikawa T. Interleukin-6 polymorphism (–634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes. Diabet Med. 2002;19(12):1000–5.CrossRefPubMed Kitamura A, Hasegawa G, Obayashi H, Kamiuchi K, Ishii M, Yano M, Yoshikawa T. Interleukin-6 polymorphism (–634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes. Diabet Med. 2002;19(12):1000–5.CrossRefPubMed
17.
go back to reference Abdolrahim-Zadeh H, Hakkakian N, Asadollahi R, Gharesifard B, Sarvari J, Kamali-Sarvestani E, Talei A. Interleukin-10 promoter polymorphisms and breast cancer risk in Iranian women. Iran J Immunol. 2005;2(3):158–65. Abdolrahim-Zadeh H, Hakkakian N, Asadollahi R, Gharesifard B, Sarvari J, Kamali-Sarvestani E, Talei A. Interleukin-10 promoter polymorphisms and breast cancer risk in Iranian women. Iran J Immunol. 2005;2(3):158–65.
18.
go back to reference Vairaktaris E, Serefoglou ZC, Yapijakis C, Agapi C, Vassiliou S, Nkenke E, Antonis V, Sofia S, Neukam FW, Patsouris E. The interleukin-18 -607A/C polymorphism is not associated with risk for oral cancer. Anticancer Res. 2007;27:4011–4.PubMed Vairaktaris E, Serefoglou ZC, Yapijakis C, Agapi C, Vassiliou S, Nkenke E, Antonis V, Sofia S, Neukam FW, Patsouris E. The interleukin-18 -607A/C polymorphism is not associated with risk for oral cancer. Anticancer Res. 2007;27:4011–4.PubMed
19.
go back to reference Coussens PM, Verman N, Coussens MA, Elftman MD, McNulty AM. Cytokine gene expression in peripheral blood mononuclear cells and tissues of cattle infected with Mycobacterium avium subsp. paratuberculosis: evidence for an inherent pro-inflammatory gene expression pattern. Infect Immunol. 2004;72:1409–22.CrossRef Coussens PM, Verman N, Coussens MA, Elftman MD, McNulty AM. Cytokine gene expression in peripheral blood mononuclear cells and tissues of cattle infected with Mycobacterium avium subsp. paratuberculosis: evidence for an inherent pro-inflammatory gene expression pattern. Infect Immunol. 2004;72:1409–22.CrossRef
20.
go back to reference Randeria SN, Thomson GJ, Nell TA, Roberts T, Pretorius E. Inflammatory cytokines in type 2 diabetes mellitus as facilitators of hypercoagulation and abnormal clot formation. Cardiovasc Diabetol. 2019;18(1):s 1-15.CrossRef Randeria SN, Thomson GJ, Nell TA, Roberts T, Pretorius E. Inflammatory cytokines in type 2 diabetes mellitus as facilitators of hypercoagulation and abnormal clot formation. Cardiovasc Diabetol. 2019;18(1):s 1-15.CrossRef
21.
go back to reference Hwang E. Polymorphisms in the 5’-UTR region of IL-10RA gene are associated with chronic kidney disease. Eur J Inflamm. 2020;18:1–11.CrossRef Hwang E. Polymorphisms in the 5’-UTR region of IL-10RA gene are associated with chronic kidney disease. Eur J Inflamm. 2020;18:1–11.CrossRef
22.
go back to reference Bid HK, Konwar R, Agrawal CG, Banerjee M. Association of IL-4 and IL-1RN (receptor antagonist) gene variants and the risk of type 2 diabetes mellitus: a study in the north Indian population. Indian J Med Sci. 2008;62:259–66.CrossRefPubMed Bid HK, Konwar R, Agrawal CG, Banerjee M. Association of IL-4 and IL-1RN (receptor antagonist) gene variants and the risk of type 2 diabetes mellitus: a study in the north Indian population. Indian J Med Sci. 2008;62:259–66.CrossRefPubMed
23.
go back to reference Jahromi M, Millward A, Demaine A. A CA repeat polymorphism of the IFN-gamma gene is associated with susceptibility to type 1 diabetes. J Interferon Cytokine Res. 2000;20:187–90.CrossRefPubMed Jahromi M, Millward A, Demaine A. A CA repeat polymorphism of the IFN-gamma gene is associated with susceptibility to type 1 diabetes. J Interferon Cytokine Res. 2000;20:187–90.CrossRefPubMed
24.
go back to reference Mittal RD, Manchanda PK. Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease. Immunogenetics. 2007;59:159–65.CrossRefPubMed Mittal RD, Manchanda PK. Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease. Immunogenetics. 2007;59:159–65.CrossRefPubMed
25.
go back to reference Masutani K, Miyake K, Nakashima H, Hirano T, Kubo M, Hirakawa M, Tsuruya K, Fukuda K, Kanai H, Otsuka T, Hirakata H, Iida M. Impact of interferon-gamma and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japanese patients. Am J Kidney Dis. 2003;41:371–9.CrossRefPubMed Masutani K, Miyake K, Nakashima H, Hirano T, Kubo M, Hirakawa M, Tsuruya K, Fukuda K, Kanai H, Otsuka T, Hirakata H, Iida M. Impact of interferon-gamma and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japanese patients. Am J Kidney Dis. 2003;41:371–9.CrossRefPubMed
26.
go back to reference Ballardie FW, Gordon MT, Sharpe PT, Darvill AM, Cheng H. Intrarenal cytokine mRNA expression and location in normal and IgA nephropathy tissue: TGF alpha, TGF beta, IGF 1, IL-4 and IL-6. Nephrol Dial Transplant. 1994;9:1545–52.PubMed Ballardie FW, Gordon MT, Sharpe PT, Darvill AM, Cheng H. Intrarenal cytokine mRNA expression and location in normal and IgA nephropathy tissue: TGF alpha, TGF beta, IGF 1, IL-4 and IL-6. Nephrol Dial Transplant. 1994;9:1545–52.PubMed
27.
go back to reference Aso Y, Yoshida N, Okumura K, Wakabayashi S, Matsutomo R, Takebayashi K, Inukai T. Coagulation and inflammation in overt diabetic nephropathy: association with hyperhomocysteinemia. Clin Chim Acta. 2004;348:139–45.CrossRefPubMed Aso Y, Yoshida N, Okumura K, Wakabayashi S, Matsutomo R, Takebayashi K, Inukai T. Coagulation and inflammation in overt diabetic nephropathy: association with hyperhomocysteinemia. Clin Chim Acta. 2004;348:139–45.CrossRefPubMed
28.
go back to reference Nakajima T, Ota N, Yoshida H, Watanabe S, Suzuki T, Emi M. Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women. Genes Immun. 1999;1:115–9.CrossRefPubMed Nakajima T, Ota N, Yoshida H, Watanabe S, Suzuki T, Emi M. Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women. Genes Immun. 1999;1:115–9.CrossRefPubMed
29.
go back to reference Scarpelli D, Cardellini M, Andreozzi F, Laratta E, Hribal ML, Marini MA, Tassi V, Lauro R, Perticone F, Sesti G. Variants of the interleukin-10 promoter gene are associated with obesity and insulin resistance but not type 2 diabetes in caucasian Italian subjects. Diabetes. 2006;55:1529–33.CrossRefPubMed Scarpelli D, Cardellini M, Andreozzi F, Laratta E, Hribal ML, Marini MA, Tassi V, Lauro R, Perticone F, Sesti G. Variants of the interleukin-10 promoter gene are associated with obesity and insulin resistance but not type 2 diabetes in caucasian Italian subjects. Diabetes. 2006;55:1529–33.CrossRefPubMed
30.
go back to reference Chang YH, Huang CN, Wu CY, Shiau MY. Association of interleukin-10 A-592C and T-819C polymorphisms with type 2 diabetes mellitus. Hum Immunol. 2005;66:1258–63.CrossRefPubMed Chang YH, Huang CN, Wu CY, Shiau MY. Association of interleukin-10 A-592C and T-819C polymorphisms with type 2 diabetes mellitus. Hum Immunol. 2005;66:1258–63.CrossRefPubMed
31.
go back to reference Kolla VK, Madhavi G, Pulla Reddy B, Srikanth Babu BM, Yashovanthi J, Valluri VL, Ramesh J, Akka J. Association of tumor necrosis factor-alpha, interferon-gamma and interleukin 10 gene polymorphisms with peripheral neuropathy in South Indian patients with type 2 diabetes. Cytokine. 2009;47:173–7.CrossRefPubMed Kolla VK, Madhavi G, Pulla Reddy B, Srikanth Babu BM, Yashovanthi J, Valluri VL, Ramesh J, Akka J. Association of tumor necrosis factor-alpha, interferon-gamma and interleukin 10 gene polymorphisms with peripheral neuropathy in South Indian patients with type 2 diabetes. Cytokine. 2009;47:173–7.CrossRefPubMed
32.
go back to reference Mtiraoui N, Ezzidi I, Kacem M, Ben Hadj Mohamed M, Chaieb M, Haj Jilani AB, Mahjoub T, Almawi WY. Predictive value of interleukin-10 promoter genotypes and haplotypes in determining the susceptibility to nephropathy in type 2 diabetes patients. Diabetes Metab Res Rev. 2009;25:57–63.CrossRefPubMed Mtiraoui N, Ezzidi I, Kacem M, Ben Hadj Mohamed M, Chaieb M, Haj Jilani AB, Mahjoub T, Almawi WY. Predictive value of interleukin-10 promoter genotypes and haplotypes in determining the susceptibility to nephropathy in type 2 diabetes patients. Diabetes Metab Res Rev. 2009;25:57–63.CrossRefPubMed
33.
go back to reference Van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG. Leiden 85 Plus S. Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. Diabetes. 2002;51:1088–92.CrossRefPubMed Van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG. Leiden 85 Plus S. Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. Diabetes. 2002;51:1088–92.CrossRefPubMed
34.
go back to reference Karjalainen J, Hulkkonen J, Nieminen MM, Huhtala H, Aromaa A, Klaukka T, Hurme M. Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma. Clin Exp Allergy. 2003;33:78–83.CrossRefPubMed Karjalainen J, Hulkkonen J, Nieminen MM, Huhtala H, Aromaa A, Klaukka T, Hurme M. Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma. Clin Exp Allergy. 2003;33:78–83.CrossRefPubMed
35.
go back to reference Yaghini N, Mahmoodi M, Asadikaram GR, Hassanshahi GH, Khoramdelazad H, Kazemi AM. Serum levels of interleukin 10 (IL-10) in patients with type 2 diabetes. Iran Red Crescent Med J. 2011;13:751–2. Yaghini N, Mahmoodi M, Asadikaram GR, Hassanshahi GH, Khoramdelazad H, Kazemi AM. Serum levels of interleukin 10 (IL-10) in patients with type 2 diabetes. Iran Red Crescent Med J. 2011;13:751–2.
36.
go back to reference Ide A, Kawasaki E, Abiru N, Sun F, Kobayashi M, Fukushima T, Takahashi R, Kuwahara H, Kita A, Oshima K, Uotani S, Yamasaki H, Yamaguchi Y, Eguchi K. Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes. J Autoimmun. 2004;22:73–8.CrossRefPubMed Ide A, Kawasaki E, Abiru N, Sun F, Kobayashi M, Fukushima T, Takahashi R, Kuwahara H, Kita A, Oshima K, Uotani S, Yamasaki H, Yamaguchi Y, Eguchi K. Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes. J Autoimmun. 2004;22:73–8.CrossRefPubMed
37.
go back to reference Tavares NA, Santos MM, Moura R, Araújo J, Guimarães R, Crovella S, Brandão L. Interleukin 18 gene promoter polymorphisms are associated with type 1 diabetes in Brazilian patients. Cytokine. 2013;62:286–9.CrossRefPubMed Tavares NA, Santos MM, Moura R, Araújo J, Guimarães R, Crovella S, Brandão L. Interleukin 18 gene promoter polymorphisms are associated with type 1 diabetes in Brazilian patients. Cytokine. 2013;62:286–9.CrossRefPubMed
38.
go back to reference Moriwaki Y, Yamamoto T, Shibutani Y, Aoki E, Tsutsumi Z, Takahashi S, Okamura H, Koga M, Fukuchi M, Hada T. Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Metabolism. 2003;52:605–8.CrossRefPubMed Moriwaki Y, Yamamoto T, Shibutani Y, Aoki E, Tsutsumi Z, Takahashi S, Okamura H, Koga M, Fukuchi M, Hada T. Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Metabolism. 2003;52:605–8.CrossRefPubMed
Metadata
Title
Cytokine gene polymorphism with type 2 diabetes and diabetic nephropathy in population from West India
Authors
Brijesh K. Dabhi
Kinnari N. Mistry
Jinal M. Thakor
Sishir Gang
Publication date
03-01-2024
Publisher
Springer India
Published in
International Journal of Diabetes in Developing Countries / Issue 4/2024
Print ISSN: 0973-3930
Electronic ISSN: 1998-3832
DOI
https://doi.org/10.1007/s13410-023-01301-5

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