Advances in Clinical and Experimental Medicine

Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 5, May, p. 651–658

doi: 10.17219/acem/91791

Publication type: original article

Language: English

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Creative Commons BY-NC-ND 3.0 Open Access

Association of coronary artery disease with toll-like receptor 4 genetic variants: A meta-analysis

Jianlong Sheng1,2,A,B,C,D,F, Jian Xu1,A,B,C,D,E,F

1 Department of Cardiology, Anhui Provincial Hospital of Anhui Medical University, Hefei, China

2 Department of Cardiology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China


Background. Toll-like receptor 4 (TLR4) plays an important role in the formation of coronary atherosclerotic plaque and the pathogenesis of coronary artery disease (CAD).
Objectives. The aim of the study was to conduct a meta-analysis assessing the relationship between 2 common genetic variants in the TLR4 gene (rs4986790 and rs4986791) and susceptibility to CAD.
Material and Methods. A systematic search of Web of Science, Embase, Scopus, PubMed, and Wanfang Med Online was undertaken. Case-control studies assessing the association of rs4986790 and rs4986791 with CAD risk were included. The odds ratio (OR) and 95% confidence interval (CI) were used as the metric of choice for the evaluation of risk.
Results. The literature search generated 427 studies, of which 14 met the inclusion criteria, for a total of 13,927 participants. Our meta-analysis revealed a significant association between rs4986791 and CAD risk in Asians using the dominant model (CT + TT vs CC: OR = 0.35, 95% CI = 0.21–0.56, p < 0.001), heterozygote contrast (CT vs CC: OR = 0.32, 95% CI = 0.19–0.57, p < 0.001) and allele contrast (T vs C: OR = 0.38, 95% CI = 0.25– 0.58, p < 0.001). No significant association between rs4986791 and CAD was observed among Caucasians. For rs4986790, the results provided no evidence of an association with CAD risk.
Conclusion. Our analysis suggests that rs4986791 is negatively associated with CAD risk in Asians but not in Caucasians. No association between rs4986790 and CAD risk was found.

Key words

polymorphism, coronary artery disease, meta-analysis, toll-like receptor 4

References (40)

  1. Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A. Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med. 2016;4(13):256.
  2. Bhatnagar P, Wickramasinghe K, Williams J, Rayner M, Townsend N. The epidemiology of cardiovascular disease in the UK 2014. Heart. 2015;101(15):1182–1189.
  3. Matyar S, Acartürk E, Attila G, Ünal I, Soyer L, Akpınar O. Gene–gene interaction of ACE I/D, endothelial nitric oxide synthase 4 a/b and ApoE does not affect coronary artery disease severity. Adv Clin Exp Med. 2014;23(2):215–223.
  4. Ha T, Liu L, Kelley J, Kao R, Williams D, Li C. Toll-like receptors: New players in myocardial ischemia/reperfusion injury. Antioxid Redox Signal. 2011;15(7):1875–1893.
  5. Roy A, Srivastava M, Saqib U, et al. Potential therapeutic targets for inflammation in Toll-like receptor 4 (TLR4)-mediated signaling pathways. Int Immunopharmacol. 2016;40:79–89.
  6. Chrzeszczyk D, Konopka T, Ziętek M. Polymorphisms of Toll-like receptor 4 as a risk factor for periodontitis: Meta-analysis. Adv Clin Exp Med. 2015;24(6):1059–1070.
  7. Sagoo GS, Little J, Higgins JP. Systematic reviews of genetic association studies. Human Genome Epidemiology Network. PLoS Med. 2009;6(3):e28.
  8. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–605.
  9. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560.
  10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188.
  11. Ameziane N, Beillat T, Verpillat P, et al. Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. ­Arterioscler Thromb Vasc Biol. 2003;23(12):e61–64.
  12. Balistreri CR, Candore G, Colonna-Romano G, et al. Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA. 2004;292(19):2339–2340.
  13. Morange PE, Tiret L, Saut N, et al. TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and the risk of coronary heart disease: The PRIME Study. Eur J Hum Genet. 2004;12(12):1041–1049.
  14. Zee RY, Hegener HH, Gould J, Ridker PM. Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis. Stroke. 2005;36(1):154–157.
  15. Hamann L, Gomma A, Schröder NW, et al. A frequent Toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med (Berl). 2005;83(6):478–485.
  16. O’Halloran AM, Stanton A, O’Brien E, Shields DC. The impact on coronary artery disease of common polymorphisms known to modulate response to pathogens. Ann Hum Genet. 2006;70(Pt 6):934–945.
  17. Koch W, Hoppmann P, Pfeufer A, Schömig A, Kastrati A. Toll-like receptor 4 gene polymorphisms and myocardial infarction: No association in a Caucasian population. Eur Heart J. 2006;27(21):2524–2529.
  18. Nebel A, Flachsbart F, Schäfer A, et al. Role of the Toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men. Mech Ageing Dev. 2007;128(5–6):409–411.
  19. Wang JN, Liu B, Song CL. To study the TLRA gene polymorphism and its association with coronary heart disease. China Prac Med. 2009;4:5–6.
  20. Džumhur A, Zibar L, Wagner J, Simundić T, Dembić Z, Barbić J. Association studies of gene polymorphisms in Toll-like receptors 2 and 4 in Croatian patients with acute myocardial infarction. Scand J Immunol. 2012;75(5):517–523.
  21. Martínez-Ríos MA, Vargas-Alarcón G, Vallejo M, et al. Toll-like receptor 4 gene polymorphisms and acute coronary syndrome: No association in a Mexican population. Arch Cardiol Mex. 2013;83(4):257–262.
  22. Golovkin AS, Ponasenko AV, Khutornaya MV, et al. Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population. Gene. 2014;550(1):101–109.
  23. Guven M, Ismailoglu Z, Batar B, et al. The effect of genetic polymorphisms of TLR2 and TLR4 in Turkish patients with coronary artery disease. Gene. 2015;558(1):99–102.
  24. Li SD, Nie Y, Sun YH, et al. Association of Toll-like receptor 2 and 4 gene polymorphisms with risk of coronary atherosclerotic artery disease in Hunan Han population [in Chinese]. J Cent South Univ (Med Sci). 2017;42(3):246–250.
  25. Arslan F, de Kleijn DP, Pasterkamp G. Innate immune signaling in cardiac ischemia. Nat Rev Cardiol. 2011;8(5):292–300.
  26. Howell KW, Meng X, Fullerton DA, Jin C, Reece TB, Cleveland JC Jr. Toll-like receptor 4 mediates oxidized LDL-induced macrophage differentiation to foam cells. J Surg Res. 2011;171(1):e27–31.
  27. Michelsen KS, Wong MH, Shah PK, et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A. 2004;101(29):10679–10684.
  28. Coenen KR, Gruen ML, Lee-Young RS, Puglisi MJ, Wasserman DH, Hasty AH. Impact of macrophage Toll-like receptor 4 deficiency on macrophage infiltration into adipose tissue and the artery wall in mice. Diabetologia. 2009;52(2):318–328.
  29. Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J. Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation. 2005;111(20):2654–2661.
  30. Fukushima R, Soejima H, Fukunaga T, et al. Expression levels of Toll-like receptor genes in coronary atherosclerotic lesions of patients with acute coronary syndrome or stable angina pectoris. Circ J. 2009;73:(8)1479–1484.
  31. Satoh S, Yada R, Inoue H, et al. Toll-like receptor-4 is upregulated in plaque debris of patients with acute coronary syndrome more than Toll-like receptor-2. Heart Vessels. 2016;31:1–5.
  32. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–1059.
  33. Prohinar P, Rallabhandi P, Weiss JP, Gioannini TL. Expression of functional D299G.T399I polymorphic variant of TLR4 depends more on coexpression of MD-2 than does wild-type TLR4. J Immunol. 2010;184(8):4362–4367.
  34. Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T. Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I. J Biol Chem. 2012;287(48):40611–40617.
  35. Chen R, Gu N, Gao Y, Cen W. TLR4 Asp299Gly (rs4986790) polymorphism and coronary artery disease: A meta-analysis. PeerJ. 2015;3:e1412.
  36. Wu BW, Zhu J, Shi HM, Jin B, Wen ZC. Association between Toll-like receptor 4 Asp299Glypolymorphism and coronary heart disease susceptibility. Braz J Med Biol Res. 2017;50(9):e6306.
  37. Boekholdt SM, Agema WR, Peters RJ, et al. Variants of Toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation. 2003;107(19):2416–2421.
  38. Holloway JW, Yang IA, Ye S. Variation in the Toll-like receptor 4 gene and susceptibility to myocardial infarction. Pharmacogenet Genomics. 2005;15(1):15–21.
  39. Edfeldt K, Bennet AM, Eriksson P, et al. Association of hypo-responsive Toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J. 2004;25(16):1447–1453.
  40. Zhou L, Zheng D, Wang S, et al. Genetic association of Toll-like receptor 4 gene and coronary artery disease in a Chinese Han population. Springerplus. 2016;5(1):1533.