INTRODUCTION: The pathogenesis of diabetes mellitus (DM) and its complications has been previously linked to elevated levels of interleukin-6 (IL-6); IL-6 triggers intracellular pathways through interaction with the IL-6 receptor (IL-6R). This study aimed to determine the association of single nucleotide polymorphisms (SNPs) IL-6 -597G/A (rs1800797), -572G/C (rs1800796), -174G/C (rs1800795), its receptor (IL-6R) Asp358Ala (+48892A/C, rs2228145) and DM or its complications in the Czech population. MATERIALS AND METHODS: In total, 669 subjects participated in this case-control study, including 167 controls, 119 patients with type 1 DM (T1DM), and 383 patients with type 2 DM (T2DM). The subjects were monitored for glycemia, glycated hemoglobin, lipid profile, glomerular filtration rate (GFR), and common complications, such as diabetic nephropathy (DN), retinopathy (DR), (poly)neuropathy (DPN), and periodontitis (P). RESULTS: Frequencies of the IL-6 and IL-6R alleles or genotypes, and IL-6 haplotypes were similar between the controls and the patients with T1DM or T2DM (P > 0.05). However, lower values of GFR were observed in diabetic patients with IL-6 -174CC homozygotes compared to other (CG and GG) genotypes (P ≤ 0.05). In addition, the IL-6R Asp358Ala variant was associated with DN (P = 0.031, OR = 1.74, 95% CI: 1.05-2.89). After subclassification according to the type of DM, the significant association of the IL-6R polymorphism with DN was only found in T1DM (P = 0.013, OR = 2.90, 95% CI: 1.25-6.71). CONCLUSIONS: This study implies a significant relationship between the IL-6R Asp358Ala polymorphism and DN in Czech T1DM patients.

Central European Institute of Technology Masaryk University Brno Czech Republic

Clinic of Stomatology Faculty of Medicine Institution Shared with St Anne's University Hospital Masaryk University Brno Czech Republic

Department of Pathophysiology Faculty of Medicine Masaryk University Brno Czech Republic

Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Biostatistics and Analyses Faculty of Medicine Masaryk University Brno Czech Republic

RECETOX Faculty of Science Masaryk University Brno Czech Republic

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American Diabetes Association . 2. Classification and diagnosis of diabetes: Standards of medical care in diabetes‐2021. Diabetes Care 2021; 44: S15–S33. PubMed

Löe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993; 16: 329–334. PubMed

Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and beta‐cell loss in type 1 diabetes. Nat Rev Endocrinol 2009; 5: 219–226. PubMed

Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860–867. PubMed

Snell‐Bergeon JK, West NA, Mayer‐Davis EJ, PubMed PMC

Wang X, Bao W, Liu J, PubMed PMC

Chen Y, Qiao Y, Pan YH, PubMed

Bowker N, Shah RL, Sharp SJ, PubMed PMC

Guzmán C, Hallal‐Calleros C, López‐Griego L,

Gabay C. Interleukin‐6 and chronic inflammation. Arthritis Res Ther 2006; 8: S3. PubMed PMC

Pal M, Febbraio MA, Whitham M. From cytokine to myokine: The emerging role of interleukin‐6 in metabolic regulation. Immunol Cell Biol 2014; 92: 331–339. PubMed

Kristiansen OP, Mandrup‐Poulsen T. Interleukin‐6 and diabetes: The good, the bad, or the indifferent? Diabetes 2005; 54: 114–124. PubMed

Dalla Vestra M, Mussap M, Gallina P, PubMed

Cotter MA, Gibson TM, Nangle MR, PubMed

Hughes FJ, Turner W, Belibasakis G, PubMed

Kishimoto T, Akira S, Taga T. Interleukin‐6 and its receptor: A paradigm for cytokines. Science 1992; 258: 593–597. PubMed

Ellingsgaard H, Ehses JA, Hammar EB, PubMed PMC

Schaper F, Rose‐John S. Interleukin‐6: Biology, signaling and strategies of blockade. Cytokine Growth Factor Rev 2015; 26: 475–487. PubMed

Lust JA, Donovan KA, Kline MP, PubMed

Garbers C, Jänner N, Chalaris A, PubMed PMC

Riethmueller S, Somasundaram P, Ehlers JC, PubMed PMC

Garbers C, Monhasery N, Aparicio‐Siegmund S, PubMed

Rafiq S, Frayling TM, Murray A, PubMed PMC

Ferreira RC, Freitag DF, Cutler AJ, PubMed PMC

Hamid YH, Rose CS, Urhammer SA, PubMed

Pérez‐Bravo F, Oyarzún AM, Soto F, PubMed

Qi L, Rifai N, Hu FB. Interleukin‐6 receptor gene variations, plasma interleukin‐6 levels, and type 2 diabetes in U.S. women. Diabetes 2007; 56: 3075–3081. PubMed

Fishman D, Faulds G, Jeffery R, PubMed PMC

Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000; 275: 18138–18144. PubMed

Papaoikonomou S, Tentolouris N, Tousoulis D, PubMed

Sharma N, Joseph R, Arun R, PubMed

Yin YW, Sun QQ, Zhang BB, PubMed

Yin YW, Sun QQ, Zhang BB, PubMed

Ebrat E, Hejazian SM, Ahmadian E, PubMed

Pacal L, Tomandl J, Svojanovsky J, PubMed

Borilova Linhartova P, Bartova J, Poskerova H, PubMed

Izakovicova Holla L, Fassmann A, Stejskalova A, PubMed

Sambrook J, Fritsch EF, Maniatis T (eds). Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1989; 9–17.

Galicia JC, Tai H, Komatsu Y, PubMed

Stančáková A, Laakso M. Genetics of type 2 diabetes. Endocr Dev 2016; 31: 203–220. PubMed

Wang Z, Xie Z, Lu Q, PubMed

Akbari M, Hassan‐Zadeh V. IL‐6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology 2018; 26: 685–698. PubMed

Maqsood M, Sharif S, Naz S, PubMed

Jin Z, Zhang Q, Liu K, PubMed

Xu WD, Zhou M, Peng H, PubMed

Cheng Z, Zhang C, Mi Y. IL‐6 gene rs1800795 polymorphism and diabetes mellitus: A comprehensive analysis involving 42,150 participants from a meta‐analysis. Diabetol Metab Syndr 2022; 14: 95. PubMed PMC

Huth C, Illig T, Herder C, PubMed PMC

Cui ZH, Lu XT, Xiao KL, PubMed

Cheng H, Zhu W, Zhu M, PubMed PMC

Lu Q, van Dam RM, Meigs JB, PubMed

Nadeem A, Mumtaz S, Naveed AK, PubMed

Patel A, MacMahon S, Chalmers J, PubMed

Perkovic V, Heerspink HL, Chalmers J, PubMed

De Boer IH, Sun W, Cleary PA, PubMed PMC

Herbert A, Liu C, Karamohamed S, PubMed

Hamid YH, Urhammer SA, Jensen DP, PubMed

Wang H, Zhang Z, Chu W, PubMed

Scheller J, Rose‐John S. The interleukin 6 pathway and atherosclerosis. Lancet 2012; 380: 338. PubMed

Rose‐John S, Jenkins BJ, Garbers C, PubMed PMC

Aparicio‐Siegmund S, Garbers Y, Flynn CM, PubMed

Ahlqvist E, van Zuydam NR, Groop LC, PubMed

Shen F, Liu D. The effects of cytokine polymorphisms on predisposition to microvascular complications of diabetes mellitus: A meta‐analysis. Int Arch Allergy Immunol 2021; 182: 1103–1112. PubMed

Feigerlová E, Battaglia‐Hsu SF. IL‐6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspectives. Cytokine Growth Factor Rev 2017; 37: 57–65. PubMed

Jo HA, Kim JY, Yang SH, PubMed PMC

Suzuki D, Miyazaki M, Naka R, PubMed

Araújo LS, Torquato BGS, da Silva CA, PubMed PMC

Wolkow PP, Niewczas MA, Perkins B, PubMed PMC

Donate‐Correa J, Martín‐Núñez E, Muros‐de‐Fuentes M, PubMed PMC

Coletta I, Soldo L, Polentarutti N, PubMed