Top

Published in:

01-12-2021 | Cytokines | Research article

Association of IL-10 (− 1082 A/G) and IL-6 (− 174 G/C) gene polymorphism with type 2 diabetes mellitus in Ethiopia population

Authors: Birhanu Ayelign, Markos Negash, Henok Andualem, Tadelo Wondemagegn, Eyuel Kassa, Tewodros Shibabaw, Yonas Akalu, Meseret Derbew Molla

Published in: BMC Endocrine Disorders | Issue 1/2021

Abstract

Background

Interleukin (IL)-6 and IL-10 are the most important cytokine with pro and anti-inflammatory activities, respectively. Dysregulation of IL-6 and IL-10 are associated with increased risk of developing Type 2 Diabetes Mellitus (T2DM). Despite this, a fundamental understanding of both cytokine gene polymorphisms with its expression is critical in understanding of cellular mechanism of insulin resistance as well as T2DM intervention. Therefore, this study aimed to assess IL-6 (− 174 G/C) and IL-10 (− 1082 A/G) gene polymorphism, and its association with T2DM, North West Ethiopia.

Methods

A comparative cross-sectional study from January to May 2018 was conducted on study participants with T2DM and apparently healthy controls. Deoxyribonucleic acid (DNA) extraction and genotyping was carried out by using amplification refractory mutation system polymerase chain reaction to detect polymorphism of IL-6 and IL-10 gene at the position − 174 and − 1082, respectively. The logistic regression model was fitted to assess the association of between cytokine gene polymorphisms and T2DM. Odds ratio with 95% CI was determined to assess the presence and strength of association between the explanatory variables and outcome variable. A P-value < 0.05 was considered as statistically significant.

Result

Participants carrying the GG genotype of IL-6 (− 174) (OR (95% CI) = 4.61 (2.07–10.54) was a high likelihood of having T2DM compared to those carrying the CC and AA genotypes. AA and AG genotypes of IL-10 (− 1082) were at lower odd of developing T2DM compared to those carrying the GG genotype. In addition, individuals carrying the G allele of IL-6 (− 174) have 2.82-fold odds of developing T2DM compared to individuals carrying the C allele (OR (95% CI) =2.81 (1.78–4.50)).

Conclusion

Our study revealed that genetic polymorphisms of IL-6 (− 174) GG genotype is the potential host genetic risk factors to T2DM. While, IL-10 (− 1082) AA genotype is negatively associated with T2DM. Therefore, IL-6 (− 174) and IL-10 (− 1082) genetic variation may be considered as a biomarker for early screening and diagnosis of T2DM.

Available only for authorised users

Punthakee Z, Goldenberg R, Katz P. Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome. Can J Diabetes. 2018;42:S10–S5. https://doi.org/10.1016/j.jcjd.2017.10.003.CrossRefPubMed

Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88–98. https://doi.org/10.1038/nrendo.2017.151.CrossRefPubMed

Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas. Diabetes Res Clin Pract. 2019;157:107843.CrossRefPubMed

Ogurtsova K, da Rocha FJ, Huang Y, Linnenkamp U, Guariguata L, Cho NH, et al. IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50. https://doi.org/10.1016/j.diabres.2017.03.024.CrossRefPubMed

IDF. Report of non-commncaiable disease.; 2015.

Agyemang C, Meeks K, Beune E, Owusu-Dabo E, Mockenhaupt FP, Addo J, de Graft Aikins A, Bahendeka S, Danquah I, Schulze MB, Spranger J, Burr T, Agyei-Baffour P, Amoah SK, Galbete C, Henneman P, Klipstein-Grobusch K, Nicolaou M, Adeyemo A, van Straalen J, Smeeth L, Stronks K. Obesity and type 2 diabetes in sub-Saharan Africans - Is the burden in today's Africa similar to African migrants in Europe? The RODAM study. BMC Med. 2016;14(1):166. https://doi.org/10.1186/s12916-016-0709-0.

Control CD. Prevention. National diabetes statistics report, 2017. Atlanta: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.

Federation I. IDF diabetes atlas eighth edition 2017; 2017.

Wolde HF, Derso T, Biks GA, Yitayal M, Ayele TA, Gelaye KA, et al. High Hidden Burden of Diabetes Mellitus among Adults Aged 18 Years and Above in Urban Northwest Ethiopia, vol. 2020; 2020.

10.

Alberti KGM, Zimmet P. Epidemiology: global burden of disease—where does diabetes mellitus fit in? Nat Rev Endocrinol. 2013;9(5):258–60. https://doi.org/10.1038/nrendo.2013.54.CrossRefPubMed

11.

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;86:100–9. https://doi.org/10.1016/j.cyto.2016.06.028.CrossRefPubMed

12.

King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008;79(8s):1527–34. https://doi.org/10.1902/jop.2008.080246.CrossRefPubMed

13.

Rivero-González A, Martín-Izquierdo E, Marín-Delgado C, Rodríguez-Muñoz A, Navarro-González JF. Cytokines in Diabetes and Diabetic Complications. In: Cytokine Effector Functions in Tissues: Elsevier; 2017. p. 119–28. https://doi.org/10.1016/B978-0-12-804214-4.00006-3.CrossRef

14.

Williams MD, Nadler JL. Inflammatory mechanisms of diabetic complications. Curr Diabetes Rep. 2007;7(3):242–8. https://doi.org/10.1007/s11892-007-0038-y.CrossRef

15.

Rodrigues KF, Pietrani NT, Bosco AA, Campos FMF, Sandrim VC, Gomes KB. IL-6, TNF-α, and IL-10 levels/polymorphisms and their association with type 2 diabetes mellitus and obesity in Brazilian individuals. Arch Endocrinol Metab. 2017;61(5):438–46. https://doi.org/10.1590/2359-3997000000254.CrossRefPubMed

16.

Gupta S, Maratha A, Siednienko J, Natarajan A, Gajanayake T, Hoashi S, et al. Analysis of inflammatory cytokine and TLR expression levels in type 2 diabetes with complications. Sci Rep. 2017;7(1):7633. https://doi.org/10.1038/s41598-017-07230-8.CrossRefPubMedPubMedCentral

17.

Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986;324(6092):73–6. https://doi.org/10.1038/324073a0.CrossRefPubMed

18.

Fisman EZ, Tenenbaum A. The ubiquitous interleukin-6: a time for reappraisal: BioMed Central; 2010.

19.

Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes. 2005;54(suppl 2):S114–S24. https://doi.org/10.2337/diabetes.54.suppl_2.S114.CrossRefPubMed

20.

Banerjee M, Saxena M. Genetic polymorphisms of cytokine genes in type 2 diabetes mellitus. World J Diabetes. 2014;5(4):493–504. https://doi.org/10.4239/wjd.v5.i4.493.CrossRefPubMedPubMedCentral

21.

Smith AJ, Humphries SE. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev. 2009;20(1):43–59. https://doi.org/10.1016/j.cytogfr.2008.11.006.CrossRefPubMed

22.

Lorente L, Martín M, Pérez-Cejas A, Barrios Y, Solé-Violán J, Ferreres J, et al. Association between interleukin-6 promoter polymorphism (−174 G/C), serum interleukin-6 levels and mortality in severe septic patients. Int J Mol Sci. 2016;17(11):1861. https://doi.org/10.3390/ijms17111861.CrossRefPubMedCentral

23.

Sharma A, Singh K, Biswas A, Ranjan R, Kishor K, Pandey H, et al. Impact of interleukin 6 promoter polymorphisms (− 174 G> C,− 572 G> C and− 597 G> a) on plasma IL-6 levels and their influence on the development of DVT: a study from India. Hematology. 2018;23(10):833–8. https://doi.org/10.1080/10245332.2018.1483546.CrossRefPubMed

24.

Stephens JW, Hurel SJ, Lowe GD, Rumley A, Humphries SE. Association between plasma IL-6, the IL6− 174G> C gene variant and the metabolic syndrome in type 2 diabetes mellitus. Mol Genet Metab. 2007;90(4):422–8, Association between plasma IL-6, the IL6 −174G>C gene variant and the metabolic syndrome in type 2 diabetes mellitus. https://doi.org/10.1016/j.ymgme.2006.10.004.CrossRefPubMed

25.

Rodrigues K, Pietrani N, Sandrim V, Vieira C, Fernandes A, Bosco A, et al. Association of a large panel of cytokine gene polymorphisms with complications and comorbidities in type 2 diabetes patients. J Diabetes Res. 2015;2015:1–9. https://doi.org/10.1155/2015/605965.CrossRef

26.

Neelofar K, Ahmad J, Ahmad A, Alam K. Study of IL4-590C/T and IL6-174G/C gene polymorphisms in type 2 diabetic patients with chronic kidney disease in north Indian population. J Cell Biochem. 2017;118(7):1803–9. https://doi.org/10.1002/jcb.25853.CrossRefPubMed

27.

Cui Z-h, Lu X-t, Xiao K-l, Chen Y, Li H-q. Association of Interleukin-6-174G/C polymorphism with the risk of diabetic nephropathy in type 2 diabetes: a meta-analysis. Curr Med Sci. 2019;39(2):250–8. https://doi.org/10.1007/s11596-019-2027-1.CrossRefPubMed

28.

Lara-Gómez RE, Moreno-Cortes ML, Muñiz-Salazar R, Zenteno-Cuevas R. Association of polymorphisms at− 174 in IL-6, and− 308 and− 238 in TNF-α, in the development of tuberculosis and type 2 diabetes mellitus in the Mexican population. Gene. 2019;702:1–7. https://doi.org/10.1016/j.gene.2019.03.050.CrossRefPubMed

29.

Fathy SA, Mohamed MR, Ali MA, EL-Helaly AE, Alattar AT. Influence of IL-6, IL-10, IFN-γ and TNF-α genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients. Biomarkers. 2019;24(1):43–55. https://doi.org/10.1080/1354750X.2018.1501761.CrossRefPubMed

30.

Howell MW. Interleukin-10 gene polymorphisms and cancer. Madame curie bioscience database [internet]: Landes Bioscience; 2013.

31.

Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012;32(1):23–63. https://doi.org/10.1615/critrevimmunol.v32.i1.30.

32.

Sabat R, Grütz G, Warszawska K, Kirsch S, Witte E, Wolk K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010;21(5):331–44. https://doi.org/10.1016/j.cytogfr.2010.09.002.CrossRefPubMed

33.

Luna GI, Silva ICRd, Sanchez MN. Association between-308G/a TNFA polymorphism and susceptibility to type 2 diabetes mellitus: a systematic review. J Diabetes Res. 2016;2016:1–6. https://doi.org/10.1155/2016/6309484.CrossRef

34.

Association AD. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018. Diabetes Care. 2018;41(Supplement 1):S13–27.CrossRef

35.

Organization WH. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: report of a WHO/IDF consultation. 2006.

36.

Gaaib JN, Nassief AF, Al-Assi A. Simple salting-out method for genomic DNA extraction from whole blood. Tikrit J Pure Sci. 2011;16(2):1813–662.

37.

Aljanabi SM, Martinez I. Universal and rapid salt-extraction of high quality genomic DNA for PCR-based techniques. Nucleic Acids Res. 1997;25(22):4692–3. https://doi.org/10.1093/nar/25.22.4692.CrossRefPubMedPubMedCentral

38.

Desjardins P, Conklin D. NanoDrop microvolume quantitation of nucleic acids. J Vis Exp. 2010;(45):e2565.

39.

Wang T, Wang L, Zhang J, Dong W. A simplified universal genomic DNA extraction protocol suitable for PCR. Genet Mol Res. 2011;10(1):519–25. https://doi.org/10.4238/vol10-1gmr1055.CrossRefPubMed

40.

Rehman K, Akash MSH, Liaqat A, Kamal S, Qadir MI, Rasul A. Role of Interleukin-6 in Development of Insulin Resistance and Type 2 Diabetes Mellitus. Crit Rev Eukaryot Gene Expr. 2017;27(3):229–36. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2017019712.

41.

Punthakee Z, Goldenberg R, Katz P. Définition, classification et diagnostic du diabète, du prédiabète et du syndrome métabolique. Can J Diabetes. 2018;42:S10–S5. https://doi.org/10.1016/j.jcjd.2017.10.003.CrossRefPubMed

42.

Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 1998;128(2):127–37. https://doi.org/10.7326/0003-4819-128-2-199801150-00009.CrossRefPubMed

43.

Granelli-Piperno A, Golebiowska A, Trumpfheller C, Siegal FP, Steinman RM. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc Natl Acad Sci. 2004;101(20):7669–74. https://doi.org/10.1073/pnas.0402431101.CrossRefPubMedPubMedCentral

44.

Romagnani S. Biology of human T H 1 and T H 2 cells. J Clin Immunol. 1995;15(3):121–9. https://doi.org/10.1007/BF01543103.CrossRefPubMed

45.

Popko K, Gorska E, Demkow U. Influence of interleukin-6 and G174C polymorphism in IL-6 gene on obesity and energy balance. Eur J Med Res. 2010;15(2):123. https://doi.org/10.1186/2047-783X-15-S2-123.CrossRefPubMedPubMedCentral

46.

Zheng S, Powell DW, Zheng F, Kantharidis P, Gnudi L. Diabetic Nephropathy: Proteinuria, Inflammation, and Fibrosis. J Diabetes Res. 2016;2016:5241549. https://doi.org/10.1155/2016/5241549.

47.

Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol. 2008;19(3):433–42. https://doi.org/10.1681/ASN.2007091048.CrossRefPubMed

48.

Saxena M, Srivastava N, Banerjee M. Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol Biol Rep. 2013;40(11):6271–9. https://doi.org/10.1007/s11033-013-2739-4.CrossRefPubMed

49.

Vozarova B, Fernández-Real J-M, Knowler WC, Gallart L, Hanson RL, Gruber JD, et al. The interleukin-6 (− 174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in native Americans and Caucasians. Hum Genet. 2003;112(4):409–13. https://doi.org/10.1007/s00439-003-0912-x.CrossRefPubMed

50.

Nadeem A, Mumtaz S, Naveed A-K, Mansoor Q, Aslam M, Siddiqui A, et al. Association of IL-6 C-174G (rs 1800795) single nucleotide polymorphism with type 2 diabetes mellitus in Pakistani population. J Pak Med Assoc. 2017;67:428.PubMed

51.

Herbert A, Liu C, Karamohamed S, Schiller J, Liu J, Yang Q, et al. The–174 IL-6 GG genotype is associated with a reduced risk of type 2 diabetes mellitus in a family sample from the National Heart, lung and blood Institute’s Framingham heart study. Diabetologia. 2005;48(8):1492–5. https://doi.org/10.1007/s00125-005-1830-3.CrossRefPubMed

52.

Bai H, Jing D, Guo A, Yin S. Association between interleukin 10 gene polymorphisms and risk of type 2 diabetes mellitus in a Chinese population. J Int Med Res. 2014;42(3):702–10. https://doi.org/10.1177/0300060513505813.CrossRefPubMed

53.

Helaly MA, Hatata ES, Abu-Elmagd M, Ibrahem EF, Alsaid A, El-Aal A, Ahmed I, Settin A. Association of IL-10 and IL-6 Gene Polymorphisms with Type 2 Diabetes Mellitus among Egyptian Patients. Eur J Gen Med. 2013;10(3):158-62. https://doi.org/10.29333/ejgm/82250.

54.

Haberle V, Stark A. Eukaryotic core promoters and the functional basis of transcription initiation. Nat Rev Mol Cell Biol. 2018;19(10):621–37. https://doi.org/10.1038/s41580-018-0028-8.CrossRefPubMedPubMedCentral

55.

Nikolov D, Burley S. RNA polymerase II transcription initiation: a structural view. Proc Natl Acad Sci. 1997;94(1):15–22. https://doi.org/10.1073/pnas.94.1.15.CrossRefPubMedPubMedCentral

56.

Butler JE, Kadonaga JT. The RNA polymerase II core promoter: a key component in the regulation of gene expression. Genes Dev. 2002;16(20):2583–92. https://doi.org/10.1101/gad.1026202.CrossRefPubMed

57.

Hampsey M. Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev. 1998;62(2):465–503. https://doi.org/10.1128/MMBR.62.2.465-503.1998.CrossRefPubMedPubMedCentral

58.

Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20. https://doi.org/10.1038/414813a.CrossRefPubMed

Title: Association of IL-10 (− 1082 A/G) and IL-6 (− 174 G/C) gene polymorphism with type 2 diabetes mellitus in Ethiopia population
Authors: Birhanu Ayelign
Markos Negash
Henok Andualem
Tadelo Wondemagegn
Eyuel Kassa
Tewodros Shibabaw
Yonas Akalu
Meseret Derbew Molla
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Cytokines
Diabetes
Type 2 Diabetes
Published in: BMC Endocrine Disorders / Issue 1/2021
Electronic ISSN: 1472-6823
DOI: https://doi.org/10.1186/s12902-021-00738-1

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Association of IL-10 (− 1082 A/G) and IL-6 (− 174 G/C) gene polymorphism with type 2 diabetes mellitus in Ethiopia population

Abstract

Background

Methods

Result

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Result

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Increasing adiposity and the presence of cardiometabolic morbidity is associated with increased Covid-19-related mortality: results from the UK Biobank

Calcium to magnesium intake ratio and non-alcoholic fatty liver disease development: a case-control study

IL-6 and IL-10 gene polymorphisms and cirrhosis of liver risk from a comprehensive analysis

Altered expression profile of BAFF receptors on peripheral blood B lymphocytes in Graves’ disease

The effect of oat bran consumption on gestational diabetes: a randomized controlled clinical trial

Does vitamin D supplementation improve ovarian reserve in women with diminished ovarian reserve and vitamin D deficiency: a before-and-after intervention study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page