Abstract
Background
Cardiovascular disease (CVD) is the leading cause of death globally, despite the recent advancements in clinical research. Early diagnosis of CVD and prevention of future complications are important for the management of CVD. In the present study, we determined the genotypic linkage of interleukin-6 (IL-6) promoters with the clinical, biochemical, and inflammatory markers of CVD in the Saudi population.
Materials and methods
The study consisted of 89 patients (male and female) with CVD who were admitted at the King Abdulaziz university hospital, Jeddah, Saudi Arabia. The biochemical parameters were evaluated using an automated chemistry analyzer, and inflammatory markers were measured using specific enzyme-linked immunosorbent assay (ELISA) kits. For genotypic analysis, Sanger sequencing was performed. We observed a statistically significant association (p < 0.05) between GG (66.29%), GC (30.34%), and CC (3.37%) genotypes at the − 174G/C (rs1800795) hotspot and neopterin levels. However, the genotypes at the − 572G/C (rs1800796) hotspot did not show any association with age, gender, obesity, diabetes, hypertension, dyslipidemia, smoking, and coronary artery status. In addition, no significant association was observed with biochemical and inflammatory markers, namely fasting blood sugar, glycated hemoglobin A1c, creatinine, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, IL-6, and C-reactive protein. The comparison between different possible genotypic groups and CVD risk factors showed a statistically significant (p < 0.05) association between the male gender and HDL with GG, rs1800795 group vs. GC, rs1800796 group. Similarly, neopterin level was also found to be significantly (p < 0.05) associated with the genotypes GC, rs1800795, and GG, rs1800796. Additionally, the male gender (p < 0.01), age (p < 0.05), serum creatinine (p < 0.001), and neopterin (p < 0.05) were found to be significantly associated with GG, rs1800795 + GG, rs1800796, GC, rs1800795 + GC, and rs1800796 GC.
Conclusion
The direct association of neopterin level with IL-6 promoter polymorphism at − 174G/C (rs1800795) hotspot indicated the role of inflammation in CVD pathogenesis in the Saudi population.
Similar content being viewed by others
References
Virani SS, Alonso A, Benjamin EJ et al (2020) Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation 141(9):e139–e596
Haukilahti MAE, Kenttä TV, Tikkanen JT et al (2021) Electrocardiographic risk markers of cardiac death: gender differences in the general population. Front Physiol 11:1829
Roth GA, Mensah GA, Johnson CO et al (2020) Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 Study. J Am Coll Cardiol 76(25):2982–3021
Nguyen MT, Fernando S, Schwarz N et al (2019) Inflammation as a therapeutic target in atherosclerosis. J Clin Med 8(8):1109
Hu D, Yin C, Luo S et al (2019) Vascular smooth muscle cells contribute to atherosclerosis immunity. Front Immunol 10:1101. https://doi.org/10.3389/fimmu.2019.01101
Malekmohammad K, Bezsonov EE, Rafieian-Kopaei M (2021) Role of lipid accumulation and inflammation in atherosclerosis: focus on molecular and cellular mechanisms. Front Cardiovasc Med 8:707529
Jabir NR, Tabrez S (2016) Cardiovascular disease management through restrained inflammatory responses. Curr Pharm Des 22(7):940–946
Soehnlein O, Libby P (2021) Targeting inflammation in atherosclerosis—from experimental insights to the clinic. Nat Rev Drug Discov 20:589–610
Fatkhullina AR, Peshkova IO, Koltsova EK (2016) The Role of cytokines in the development of atherosclerosis. Biochemistry 81(11):1358–1370
Kurilenko N, Fatkhullina AR, Mazitova A et al (2021) Act locally, act globally—microbiota, barriers, and cytokines in atherosclerosis. Cells 10(2):348
Gager GM, Biesinger B, Hofer F et al (2020) Interleukin-6 level is a powerful predictor of long-term cardiovascular mortality in patients with acute coronary syndrome. Vascul Pharmacol 135:106806
Didion SP (2017) Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature. Int J Mol Sci 18(12):2563
Kang S, Kishimoto T (2021) Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Exp Mol Med 53(7):1116–1123
Villar-Fincheira P, Sanhueza-Olivares F, Norambuena-Soto I et al (2021) Role of interleukin-6 in vascular health and disease. Front Mol Biosci 8:79
Yang C, Deng Z, Li J et al (2021) Meta-analysis of the relationship between interleukin-6 levels and the prognosis and severity of acute coronary syndrome. Clinics 76:e2690
Firoz CK, Jabir NR, Kamal MA et al (2015) Neopterin: an immune biomarker of coronary artery disease and its association with other CAD markers. IUBMB Life 67(6):453–459
Jabir NR, Siddiqui AN, Firoz CK et al (2015) Current updates on therapeutic advances in the management of cardiovascular diseases. Curr Pharm Des 22(5):566–571
Tabrez S, Jabir NR, Firoz CK et al (2017) Estimation of Interleukin-1β promoter (-31 C/T and –511 T/C) polymorphisms and its level in coronary artery disease patients. J Cell Biochem 118(9):2977–2982
Jabir NR, Firoz CK, Kamal MA et al (2016) Assessment of genetic diversity in IL-6 and RANTES promoters and their level in Saudi coronary artery disease (CAD) patients. J Clin Lab Anal 31(5):e22092
Tabrez S, Jabir NR, Zughaibi TA et al (2021) Genotyping of interleukins-18 promoters and their correlation with coronary artery stenosis in Saudi population. Mol Biol Rep 48(10):6695–6702
Khera AV, Kathiresan S (2017) Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 18(6):331–344
Zhang X-L, Xie J, Lan R-F et al (2020) Genetic basis and genotype-phenotype correlations in han chinese patients with idiopathic dilated cardiomyopathy. Sci Rep 10:2226. https://doi.org/10.1038/s41598-020-58984-7
Kaur N, Singh J, Reddy S et al (2020) ANRIL rs1333049 C/G polymorphism and coronary artery disease in a North Indian population-gender and age specific associations. Genet Mol Biol 43(1):e20190024. https://doi.org/10.1590/1678-4685-GMB-2019-0024
Zhao H, Hu S, Rong J (2020) Gene polymorphism associated with Angiotensinogen(M235T), Endothelial lipase (584C/T) and susceptibility to coronary artery disease: a meta-analysis. bioRxiv 2020.04.24.059295
Sirotina S, Ponomarenko I, Kharchenko A et al (2018) A novel polymorphism in the promoter of the CYP4A11 gene is associated with susceptibility to coronary artery disease. Dis Mark 2018:5812802. https://doi.org/10.1155/2018/
Liu H, Wang H (2016) Early detection system of vascular disease and its application prospect. Biomed Res Int 2016:1723485. https://doi.org/10.1155/2016/
Cavalcante JEA, de Sousa ELH, de Oliveira RR et al (2020) Interleukin-18 promoter –137 G/C polymorphism (rs187238) is associated with biochemical markers of renal function and cardiovascular disease in type 2 diabetes patients. Clin Biochem 80:1–7
Zheng G-H, Chen H-Y, Xiong S-Q (2012) Polymorphisms of −174G>C and −572G>C in the interleukin 6 (IL-6) gene and coronary heart disease risk: a meta-analysis of 27 research studies. PLoS ONE 7(4):e34839
Sie MPS, Sayed-Tabatabaei FA, Oei H-HS et al (2006) Interleukin 6–174 G/C promoter polymorphism and risk of coronary heart disease. Arterioscler Thromb Vasc Biol 26(1):212–217
Spielman RS, Bastone LA, Burdick JT et al (2007) Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet 39(2):226–231
Craig DG, Lee P, Pryde EA et al (2013) Serum neopterin and soluble CD163 as markers of macrophage activation in paracetamol (acetaminophen)-induced human acute liver injury. Aliment Pharmacol Ther 38(11–12):1395–1404
Grammer TB, Fuchs D, Boehm BO et al (2009) Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography in the ludwigshafen risk and cardiovascular health study. Clin Chem 55(6):1135–1146
Pihlstrøm H, Mjøen G, März W et al (2014) Neopterin is associated with cardiovascular events and all-cause mortality in renal transplant patients. Clin Transpl 28(1):111–119
Watanabe T (2021) Neopterin derivatives-a novel therapeutic target rather than biomarker for atherosclerosis and related diseases. Vasa 50(3):165–173
Nada SZ (2017) Neopterin, interleukin-6, and non HDL-C as predictors for cardiac disease among type 2 diabetic women with and without renal complications. Iraq Med J 1(3):79–82
Acknowledgements
This project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under Grant Number (G: 332–141–1442). The authors, therefore, acknowledge with thanks DSR technical and financial support.
Author information
Authors and Affiliations
Contributions
S.T, T.A.Z and N.R.J performed the experiments. M.S. was involved in the analysis of the sequenced data. All authors reviewed the final draft of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The author(s) declare that there is no conflict of interest regarding the publication of this article.
Ethical approval
The current study was conducted in compliance with the Declaration of Helsinki, and the study protocol was approved by the institutional ethical committee (Reference No. 84–16).
Consent to participate
Written and properly informed consent was acquired from each individual involved in the study before the commencement of sample collection.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tabrez, S., Jabir, N.R., Zughaibi, T.A. et al. Association of IL-6 promoter polymorphism hotspots (− 174G/C and − 572G/C) with cardiovascular disease risk factors. Mol Biol Rep 49, 2265–2272 (2022). https://doi.org/10.1007/s11033-021-07048-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-021-07048-8