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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

IL-1β and IL-1Ra Variant Profiles in Turkish Patients with Diabetic Peripheral Neuropathy

Author(s): Ayse Feyda Nursal*, Ahmet Inanir, Aydın Rustemoglu, Suheyla Uzun, Kubra Sahin and Serbulent Yigit

Volume 19, Issue 2, 2019

Page: [150 - 158] Pages: 9

DOI: 10.2174/1871530318666181022165048

Price: $65

Abstract

Background: Diabetic peripheral neuropathy (DPN) is one of the most common complications of Type 2 diabetes mellitus (T2DM). This study was conducted to investigate the possible association between interleukin-1β (IL-1β) rs16944 /IL-1 receptor antagonist (IL-1Ra) VNTR variants and genetic susceptibility to DPN in a Turkish cohort.

Methods: A total of 200 subjects were enrolled in this study, 98 patients with DPN and 102 cases of age and sex-matched healthy controls. Genotyping was performed for all individuals using PCR-RFLP analysis.

Results: IL-1β rs16944 CC genotype had a 3.20-fold increased risk for DPN (p=0.0003, OR=3.20, 95% Cl:1.72-5.96). IL-1β rs16944 CT genotype was higher in healthy control than patients (p=0.004). IL-1β rs16944 C allele was higher in the patient group compared to controls while T allele was lower in patients than controls (p=0.003). IL-1Ra VNTR a1/a1 and a2/a2 genotypes were lower in DPN patients while a1/a2 genotype was higher in patients (p=0.045). The patients carrying a1/T haplotype had decreased risk of DPN than control groups (p=0.004). The patients carrying a2/a2 genotype had lower HDL level (p=0.039). The subjects carrying a2/a2 genotype had higher total cholesterol level while the subjects carrying a1/a2 genotype had lower total cholesterol (p=0.026 and p=0.037, respectively). IL-1Ra a1 allele was associated with higher HDL level (p=0.041).

Conclusion: Findings of this study indicated that the IL-1β rs16944 and IL-1Ra VNTR variants are probably to be associated with susceptibility DPN risk in a Turkish cohort.

Keywords: Type 2 diabetes mellitus, diabetic peripheral neuropathy, interleukin-1β, interleukin-1Ra, IL-1Ra VNTR variants, DPN risk.

Graphical Abstract
[1]
Rodrigues, K.F.; Pietrani, N.T.; Sandrim, V.C.; Vieira, C.M.; Fernandes, A.P.; Bosco, A.A.; Gomes, K.B. Association of a large panel of cytokine gene polymorphisms with complications and comorbidities in type 2 diabetes patients. J. Diabetes Res., 2015, 2015, 605965.
[2]
Wang, H.; Fan, D.; Zhang, Y. Angiogenin gene polymorphism: A risk factor for diabetic peripheral neuropathy in the northern Chinese Han population. Neural Regen. Res., 2013, 8, 3434-3440.
[3]
Dandona, P.; Aljada, A.; Bandyopadhyay, A. Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol., 2004, 25, 4-7.
[4]
Garlanda, C.; Dinarello, C.A.; Mantovani, A. The interleukin-1 family: Back to the future. Immunity, 2013, 39, 1003-1018.
[5]
Bidwell, J.; Keen, L.; Gallagher, G.; Kimberly, R.; Huizinga, T.; McDermott, M.F.; Oksenberg, J.; McNicholl, J.; Pociot, F.; Hardt, C.; D’Alfonso, S. Cytokine gene polymorphism in human disease: On-balance line databases. Genes Immun., 1999, 1, 3-19.
[6]
Achyut, B.R.; Srivastava, A.; Bhattacharya, S.; Mittal, B. Genetic association of interleukin-1beta (-511C/T) and interleukin-1 receptor antagonist (86 bp repeat) polymorphisms with Type 2 diabetes mellitus in North Indians. Clin. Chim. Acta, 2007, 377, 163-169.
[7]
Lee, J.M.; Kang, Y.R.; Park, S.H.; Cha, S.I.; Kim, J.S.; Kang, H.K.; Lee, W.K.; Kim, M.J.; Kim, C.H.; Kim, N.S.; Jung, T.H.; Park, J.Y. Polymorphisms in interleukin-1B and its receptor antagonist genes and the risk of chronic obstructive pulmonary disease in a Korean population: A case-control study. Respir. Med., 2008, 102, 1311-1320.
[8]
Dyck, P.J.; Litchy, W.J.; Lehman, K.A.; Hokanson, J.L.; Low, P.A.; O’Brien, P.C. Variables influencing neuropathic endpoints: The rochester diabetic neuropathy study of healthy subjects. Neurology, 1995, 45, 1115-1121.
[9]
Rad, R.; Prinz, C.; Neu, B.; Neuhofer, M.; Zeitner, M.; Voland, P.; Becker, I.; Schepp, W.; Gerhard, M. Synergistic effect of Helicobacter pylori virulencefactors and interleukin-1 polymorphisms for the development of severehistological changes in the gastric mucosa. J. Infect. Dis., 2003, 188, 272-281.
[10]
Tarlow, J.K.; Blakemore, A.I.; Lennard, A.; Solari, R.; Hughes, H.N.; Steinkasserer, A.; Duff, G.W. Polymorphism in human IL-1receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum. Genet., 1993, 91, 403-404.
[11]
Ghavimi, R.; Sharifi, M.; Mohaghegh, M.A.; Mohammadian, H.; Khadempar, S.; Rezaei, H. Lack of association between rs1800795 (-174 G/C) polymorphism in the promoter region of interleukin-6 gene and susceptibility to type 2 diabetes in Isfahan population. Adv. Biomed. Res., 2016, 5, 18.
[12]
Alexandraki, K.; Piperi, C.; Kalofoutis, C.; Singh, J.; Alaveras, A.; Kalofoutis, A. Inflammatory process in type 2 diabetes: The role of cytokines. Ann. N. Y. Acad. Sci., 2006, 1084, 89-117.
[13]
Pickup, J.C.; Chusney, G.D.; Thomas, S.M.; Burt, D. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci., 2000, 67, 291-300.
[14]
Mirza, S.; Hossain, M.; Mathews, C.; Martinez, P.; Pino, P.; Gay, J.L.; Rentfro, A.; McCormick, J.B.; Fisher-Hoch, S.P. Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: A cross-sectional study. Cytokine, 2012, 57, 136-142.
[15]
Hu, F.B.; Meigs, J.B.; Li, T.Y.; Rifai, N.; Manson, J.E. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes, 2004, 53, 693-700.
[16]
Pradhan, A.D.; Manson, J.E.; Rifai, N.; Buring, J.E.; Ridker, P.M. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, 2001, 286, 327-334.
[17]
Duncan, B.B.; Schmidt, M.I.; Pankow, J.S.; Ballantyne, C.M.; Couper, D.; Vigo, A.; Hoogeveen, R.; Folsom, A.R.; Heiss, G. Atherosclerosis risk in communities study. Low-grade systemic inflammation and the development of type 2 diabetes: The atherosclerosis risk in communities study. Diabetes, 2003, 52, 1799-1805.
[18]
Cameron, N.E.; Cotter, M.A. Pro-inflammatory mechanisms in diabetic neuropathy: Focus on the nuclear factor kappa B pathway. Curr. Drug Targets, 2008, 9, 60-67.
[19]
Doupis, J.; Lyons, T.E.; Wu, S.; Gnardellis, C.; Dinh, T.; Veves, A. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J. Clin. Endocrinol. Metab., 2009, 9, 2157-2163.
[20]
Hur, J.; Sullivan, K.A.; Pande, M.; Hong, Y.; Sima, A.A.; Jagadish, H.V.; Kretzler, M.; Feldman, E.L. The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain, 2011, 134, 3222-3235.
[21]
Papanas, N.; Ziegler, D. Risk factors and comorbidities in diabetic neuropathy: An update 2015. Rev. Diabet. Stud., 2015, 12, 48-62.
[22]
Herder, C.; Bongaerts, B.W.; Rathmann, W.; Heier, M.; Kowall, B.; Koenig, W.; Thorand, B.; Roden, M.; Meisinger, C.; Ziegler, D. Differential association between biomarkers of subclinical inflammation and painful polyneuropathy. Results from the KORA F4 Study. Diabetes Care, 2015, 38, 91-96.
[23]
Herder, C.; Bongaerts, B.W.; Rathmann, W.; Heier, M.; Kowall, B.; Koenig, W.; Thorand, B.; Roden, M.; Meisinger, C.; Ziegler, D. Association of subclinical inflammation with polyneuropathy in the older population: KORA F4 Study. Diabetes Care, 2013, 36, 3663-3670.
[24]
Carter, K.W.; Hung, J.; Powell, B.L.; Wiltshire, S.; Foo, B.T.; Leow, Y.C.; McQuillan, B.M.; Jennens, M.; McCaskie, P.A.; Thompson, P.L.; Beilby, J.P.; Palmer, L.J. Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population. Hum. Genet., 2008, 124, 199-206.
[25]
Luotola, K.; Pääkkönen, R.; Alanne, M.; Lanki, T.; Moilanen, L.; Surakka, I.; Pietilä, A.; Kähönen, M.; Nieminen, M.S.; Kesäniemi, Y.A.; Peters, A.; Jula, A.; Perola, M.; Salomaa, V. Health 2000 airgene study groups. Association of variation in the interleukin-1 gene family with diabetes and glucose homeostasis. J. Clin. Endocrinol. Metab., 2009, 94, 4575-4583.
[26]
Bendtzen, K.; Mandrup-Poulsen, T.; Nerup, J.; Nielsen, J.H.; Dinarello, C.A. Svenson. M. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science, 1986, 232, 1545-1547.
[27]
Mandrup-Poulsen, T.; Bendtzen, K.; Nerup, J.; Dinarello, C.A.; Svenson, M.; Nielsen, J.H. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia, 1986, 29, 63-67.
[28]
Maedler, K.; Sergeev, P.; Ris, F.; Oberholzer, J.; Joller-Jemelka, H.I.; Spinas, G.A.; Kaiser, N.; Halban, P.A.; Donath, M.Y. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest., 2002, 110, 851-860.
[29]
Liu, C.; Feng, X.; Li, Q.; Wang, Y.; Li, Q.; Hua, M. Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis. Cytokine, 2016, 86, 100-109.
[30]
Saxena, M.; Agrawal, C.G.; Srivastava, N.; Banerjee, M. Interleukin-6 (IL-6)-597 A/G (rs1800797) & -174 G/C (rs1800795) gene polymorphisms in type 2 diabetes. Indian J. Med. Res., 2014, 140, 60-68.
[31]
Patel, R.; Dwivedi, M.; Mansuri, M.S. Ansarullah, Laddha, N.C.; Thakker, A.; Ramachandran, A.V.; Begum, R. Association of Neuropeptide-Y (NPY) and Interleukin-1beta (IL1B), genotype-phenotype correlation and plasma lipids with type-ii diabetes. PLoS One, 2016, 11, e0164437.
[32]
Vasudevan, R.; Ismail, P.; Stanslas, J.; Shamsudin, N. C-511T polymorphism of interleukin-1β gene is not associated in Type 2 diabetes mellitus-a study in malaysian population. J. Med. Sci., 2008, 8, 216-221.
[33]
Navarro-González, J.F.; Mora-Fernández, C. The role of inflammatory cytokines in diabetic nephropathy. J. Am. Soc. Nephrol., 2008, 19, 433-442.
[34]
Lee, S.H.; Ihm, C.G.; Sohn, S.D.; Lee, T.W.; Kim, M.J.; Koh, G.; Oh, S.J.; Woo, J.T.; Kim, S.W.; Kim, J.W.; Kim, Y.S.; Lee, B.C.; Kim, S.D.; Cho, B.S.; Lee, H.J.; Chung, J.H. Polymorphisms in interleukin-1 beta and Interleukin-1 receptor antagonist genes are associated with kidney failure in Korean patients with type 2 diabetes mellitus. Am. J. Nephrol., 2004, 24, 410-414.
[35]
Meier, C.A.; Bobbioni, E.; Gabay, C.; Assimacopoulos-Jeannet, F.; Golay, A.; Dayer, J.M. IL-1 receptor antagonist serum levels are increased in human obesity: A possible link to the resistance to leptin? J. Clin. Metab. Endocrinol., 2002, 87, 1184-1188.
[36]
Larsen, C.M.; Faulenbach, M.; Vaag, A.; Vølund, A.; Ehses, J.A.; Seifert, B.; Mandrup-Poulsen, T.; Donath, M.Y. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med., 2007, 356, 1517-1526.
[37]
Settin, A.; Ismail, A.; El-Magd, M.A.; El-Baz, R.; Kazamel, A. Gene polymorphisms of TNF-alpha-308 (G/A), IL-10(-1082) (G/A), IL-6(-174) (G/C) and IL-1Ra (VNTR) in Egyptian cases with type 1 diabetes mellitus. Autoimmunity, 2009, 42, 50-55.
[38]
Al-Safar, H.; Kamal, W.; Hassoun, A.; Almahmeed, W.; Rais, N. Combined association analysis of interleukin 1-receptor antagonist (IL-1RN) variable number of tandem repeat (VNTR) and Haptoglobin 1/2 polymorphisms with type 2 diabetes mellitus risk. J. Diabetes Metab. Disord., 2016, 15, 10.
[39]
Singh, U.; Indurkar, P.; Saxena, A.; Mishra, P.; Tripathi, A.K. Association of IL-1RN polymorphism with diabetes type 2 in Central Indian Population. J. Biol. Sci. Med., 2016, 2, 6-13.
[40]
Bid, H.K.; Konwar, R.; Agrawal, C.G.; 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, 259-266.
[41]
Tarlow, J.K.; Cork, M.J.; Clay, F.E.; Schmitt-Egenolf, M.; Crane, A.M.; Stierle, C.; Boehncke, W.H.; Eiermann, T.H.; Blakemore, A.I.; Bleehen, S.S.; Sterry, W.; Duff, G.V. Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis. Br. J. Dermatol., 1997, 136, 147-148.
[42]
Kamenarska, Z.; Dzhebir, G.; Hristova, M.; Savov, A.; Vinkov, A.; Kaneva, R.; Mitev, V.; Dourmishev, L. IL-1RN VNTR polymorphism in adult dermatomyositis and systemic lupus erythematosus. Dermatol. Res. Pract., 2014, 2014, 953597.
[43]
Blakemore, A.I.; Cox, A.; Gonzalez, A.M.; Maskil, J.K.; Hughes, M.E.; Wilson, R.M.; Ward, J.D.; Duff, G.W. Interleukin-1 receptor antagonist allele (IL1RN*2) associated with nephropathy in diabetes mellitus. Hum. Genet., 1996, 97, 369-374.

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