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Structural Genomic Variation in Pattern Recognition Receptors and Cardiovascular Diseases

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Genomics of Pattern Recognition Receptors

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Abstract

Atherosclerosis, manifesting itself as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic progressive inflammatory disease characterized by the accumulation of lipid and fibrous elements in arterial walls, which is driven by responses of both innate and adaptive immunity. As a possible trigger, several studies have suggested that various bacteria and viruses are associated with atherosclerotic diseases. The local vascular immune response against these infectious agents is performed mainly via the pattern recognition receptors. It is known that alleles of the wild-type TLR4 Asp299Gly and Thr399Ile polymorphisms are associated with the progression of atherosclerosis, while carriers of the 299Gly and 399Thr minor alleles which diminish the TLR4-mediated immune response are characterized by a lower level of circulating inflammatory markers and by smaller carotid intima-media thickness. However, minor allele carriers have an elevated risk of myocardial infarction, while wild-type allele possesses a protective effect. It seems to be that population features play the major role in the determination of 299Gly-mediated myocardial infarction risk modification. Concerning various types of cardiovascular events, all positive or negative statistically significant associations were found only for myocardial infarction, whereas two studies in which the role of Asp299Gly polymorphism in stroke development was investigated did not find any association. Regarding other polymorphisms, the number of performed studies is much lower, and the results are inconclusive.

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References

  1. Hansson GK (2005) Mechanisms of disease: inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695

    Article  PubMed  CAS  Google Scholar 

  2. Hansson GK, Robertson AK, Soderberg-Naucler C (2006) Inflammation and atherosclerosis. Annu Rev Pathol 1:297–329

    Article  PubMed  CAS  Google Scholar 

  3. Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 27:165–197

    Article  PubMed  CAS  Google Scholar 

  4. Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17(11):1410–1422

    Article  PubMed  CAS  Google Scholar 

  5. Steinberg D (2002) Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 8(11):1211–1217

    Article  PubMed  CAS  Google Scholar 

  6. Zernecke A, Bot I, Djalali-Talab Y, Shagdarsuren E, Bidzhekov K, Meiler S et al (2008) Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res 102(2):209–217

    Article  PubMed  CAS  Google Scholar 

  7. Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O (2010) Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 122(18):1837–1845

    Article  PubMed  CAS  Google Scholar 

  8. Manthey HD, Zernecke A (2011) Dendritic cells in atherosclerosis: functions in immune regulation and beyond. Thromb Haemost 106(5):772–778

    Article  PubMed  CAS  Google Scholar 

  9. Weber C, Meiler S, Döring Y, Koch M, Drechsler M, Megens RT et al (2011) CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest 121(7):2898–2910

    Article  PubMed  CAS  Google Scholar 

  10. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809

    Article  PubMed  CAS  Google Scholar 

  11. Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917):868–874

    Article  PubMed  CAS  Google Scholar 

  12. Weber C, Zernecke A, Libby P (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8(10):802–815

    Article  PubMed  CAS  Google Scholar 

  13. Benditt EP, Barrett T, McDougall JK (1983) Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci USA. 80:6386–6389

    Article  PubMed  CAS  Google Scholar 

  14. Valtonen VV (1991) Infection as a risk factor for infarction and atherosclerosis. Ann Med 23(5):539–543

    Article  PubMed  CAS  Google Scholar 

  15. Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G (1993) Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet 341(8840):255–259

    Article  PubMed  CAS  Google Scholar 

  16. Rosenfeld ME, Campbell LA (2011) Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 106(5):858–867

    Article  PubMed  CAS  Google Scholar 

  17. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347(3):185–192

    Article  PubMed  CAS  Google Scholar 

  18. Edfeldt K, Bennet AM, Eriksson P, Frostegård J, Wiman B, Hamsten A, Hansson GK, de Faire U, Yan ZQ (2004) Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J 25(16):1447–1453

    Article  PubMed  CAS  Google Scholar 

  19. Vink A, Schoneveld AH, van der Meer JJ, van Middelaar BJ, Sluijter JP, Smeets MB, Quax PH, Lim SK, Borst C, Pasterkamp G, de Kleijn DP (2002) In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation 106(15):1985–1990

    Article  PubMed  CAS  Google Scholar 

  20. Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1(2):135–145

    Article  PubMed  CAS  Google Scholar 

  21. Danenberg HD, Welt FG, Walker M 3rd, Seifert P, Toegel GS, Edelman ER (2002) Systemic inflammation induced by lipopolysaccharide increases neointimal formation after balloon and stent injury in rabbits. Circulation 105(24):2917–2922

    Article  PubMed  CAS  Google Scholar 

  22. Falk E, Shah PK, Fuster V (1995) Coronary plaque disruption. Circulation 92(3):657–671

    Article  PubMed  CAS  Google Scholar 

  23. Libby P (1995) Molecular bases of the acute coronary syndromes. Circulation 91(11):2844–2850

    Article  PubMed  CAS  Google Scholar 

  24. Sasu S, LaVerda D, Qureshi N, Golenbock DT, Beasley D (2001) Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via toll-like receptor 4 and p44/p42 mitogen-activated protein kinase activation. Circ Res 89(3):244–250

    Article  PubMed  CAS  Google Scholar 

  25. Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ (2002) Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105(10):1158–1161

    PubMed  CAS  Google Scholar 

  26. Boekholdt SM, Agema WR, Peters RJ, Zwinderman AH, van der Wall EE, Reitsma PH, Kastelein JJ, Jukema JW (2003) Regression growth evaluation statin study group. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation 107(19):2416–2421

    Article  PubMed  CAS  Google Scholar 

  27. Ameziane N, Beillat T, Verpillat P, Chollet-Martin S, Aumont MC, Seknadji P, Lamotte M, Lebret D, Ollivier V, de Prost D (2003) Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol 23(12):e61–e64

    Article  PubMed  Google Scholar 

  28. Balistreri CR, Candore G, Colonna-Romano G, Lio D, Caruso M, Hoffmann E, Franceschi C, Caruso C (2004) Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 292(19):2339–2340

    PubMed  CAS  Google Scholar 

  29. Morange PE, Tiret L, Saut N, Luc G, Arveiler D, Ferrieres J, Amouyel P, Evans A, Ducimetiere P, Cambien F, Juhan-Vague I, PRIME Study Group (2004) 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 12(12):1041–1049

    Article  PubMed  CAS  Google Scholar 

  30. Reismann P, Lichy C, Rudofsky G, Humpert PM, Genius J, Si TD, Dörfer C, Grau AJ, Hamann A, Hacke W, Nawroth PP, Bierhaus A (2004) Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia. J Neurol 251(7):853–858

    PubMed  CAS  Google Scholar 

  31. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, Maggi FM, Catapano AL (2005) Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med 258(1):21–27

    Article  PubMed  CAS  Google Scholar 

  32. Zee RY, Hegener HH, Gould J, Ridker PM (2005) Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis. Stroke 36(1):154–157

    Article  PubMed  CAS  Google Scholar 

  33. Holloway JW, Yang IA, Ye S (2005) Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction. Pharmacogenet Genomics 15(1):15–21

    Article  PubMed  CAS  Google Scholar 

  34. Lin YC, Chang YM, Yu JM, Yen JH, Chang JG, Hu CJ (2005) Toll-like receptor 4 gene C119A but not Asp299Gly polymorphism is associated with ischemic stroke among ethnic Chinese in Taiwan. Atherosclerosis 180(2):305–309

    Article  PubMed  CAS  Google Scholar 

  35. Koch W, Hoppmann P, Pfeufer A, Schömig A, Kastrati A (2006) Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur Heart J 27(21):2524–2529

    Article  PubMed  CAS  Google Scholar 

  36. Candore G, Aquino A, Balistreri CR, Bulati M, Di Carlo D, Grimaldi MP, Listì F, Orlando V, Vasto S, Caruso M, Colonna-Romano G, Lio D, Caruso C (2006) Inflammation, longevity, and cardiovascular diseases: role of polymorphisms of TLR4. Ann NY Acad Sci 1067:282–287

    Article  PubMed  CAS  Google Scholar 

  37. Balistreri CR, Candore G, Listì F, Fazio T, Gangi S, Incalcaterra E, Caruso M, Vecchi ML, Lio D, Caruso C (2007) Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful aging. Ann NY Acad Sci 1119:203–207

    Article  PubMed  CAS  Google Scholar 

  38. Hernesniemi J, Lehtimäki T, Rontu R, Islam MS, Eklund C, Mikkelsson J, Ilveskoski E, Kajander O, Goebeler S, Viiri LE, Hurme M, Karhunen PJ (2006) Toll-like receptor 4 polymorphism is associated with coronary stenosis but not with the occurrence of acute or old myocardial infarctions. Scand J Clin Lab Invest 66(8):667–675

    Article  PubMed  CAS  Google Scholar 

  39. Lalouschek W, Schillinger M, Hsieh K, Endler G, Greisenegger S, Marculescu R, Lang W, Wagner O, Cheng S, Mannhalter C (2006) Polymorphisms of the inflammatory system and risk of ischemic cerebrovascular events. Clin Chem Lab Med 44(8):918–923

    Article  PubMed  CAS  Google Scholar 

  40. De Staercke C, Lally C, Austin H, Winston C, Dowling N, Williams B, Hooper WC (2007) The lack of association between four point mutations in the promoter region of the toll-like 4 receptor gene and myocardial infarction. Thromb Res 119(1):105–110

    Article  PubMed  Google Scholar 

  41. Nebel A, Flachsbart F, Schäfer A, Nothnagel M, Nikolaus S, Mokhtari NE, Schreiber S (2007) Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men. Mech Ageing Dev 128(5–6):409–411

    Article  PubMed  CAS  Google Scholar 

  42. Balistreri CR, Candore G, Mirabile M, Lio D, Caimi G, Incalcaterra E, Caruso M, Hoffmann E, Caruso C (2008) TLR2 and age-related diseases: potential effects of Arg753Gln and Arg677Trp polymorphisms in acute myocardial infarction. Rejuvenation Res 11(2):293–296

    Article  PubMed  CAS  Google Scholar 

  43. Enquobahrie DA, Smith NL, Bis JC, Carty CL, Rice KM, Lumley T, Hindorff LA, Lemaitre RN, Williams MA, Siscovick DS, Heckbert SR, Psaty BM (2008) Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke. Am J Cardiol 101(12):1683–1688

    Article  PubMed  CAS  Google Scholar 

  44. Lima-Neto LG, Hirata RD, Luchessi AD, Silbiger VN, Pastorelli CP, Sampaio MF, Armaganijan D, Rezende AA, Doi SQ, Hirata MH (2009) Detection of the TLR4 1196C> T polymorphism by mismatched-polymerase chain reaction using plasmid DNA as internal control in restriction fragment length polymorphism assays. Genet Test Mol Biomark 13(3):343–347

    Article  CAS  Google Scholar 

  45. Tiszlavicz Z, Somogyvári F, Kocsis AK, Szolnoki Z, Sztriha LK, Kis Z, Vécsei L, Mándi Y (2009) Relevance of the genetic polymorphism of NOD1 in Chlamydia pneumoniae seropositive stroke patients. Eur J Neurol 16(11):1224–1229

    Article  PubMed  CAS  Google Scholar 

  46. Incalcaterra E, Caruso M, Balistreri CR, Candore G, Lo Presti R, Hoffmann E, Caimi G (2010) Role of genetic polymorphisms in myocardial infarction at young age. Clin Hemorheol Microcirc 46(4):291–298

    PubMed  CAS  Google Scholar 

  47. Yuan M, Xia J, Ma L, Xiao B, Yang Q (2010) Lack of the Toll-Like receptor 4 gene polymorphisms Asp299Gly and Thr399ile in a Chinese population. Int J Neurosci 120(6):415–420

    Article  PubMed  CAS  Google Scholar 

  48. Džumhur A, Zibar L, Wagner J, Simundić T, Dembić Z, Barbić J (2012) Association studies of gene polymorphisms in toll-like receptors 2 and 4 in Croatian patients with acute myocardial infarction. Scand J Immunol 75(5):517–523

    Article  PubMed  Google Scholar 

  49. Park HJ, Kim SK, Yun DH, Kim DH, Chon J, Kim JW, Chung JH (2012) Association of toll-like receptor 2 polymorphisms with National Institute of Health Stroke Scale scores of ischemic stroke patients. J Mol Neurosci 46(3):536–540

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Epidemiology, Kemerovo State Medical Academy, Voroshilova Street 22A, Kemerovo, 650029, Russia

    Anton G. Kutikhin

  2. Siberian Branch, Res Inst Cardiovascular Diseases, Russian Academy of Medical Sciences, Sosnovy Blvd. 6, Kemerovo, 650002, Russia

    Arseniy E. Yuzhalin

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Correspondence to Anton G. Kutikhin .

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Kutikhin, A.G., Yuzhalin, A.E. (2013). Structural Genomic Variation in Pattern Recognition Receptors and Cardiovascular Diseases. In: Genomics of Pattern Recognition Receptors. Springer, Basel. https://doi.org/10.1007/978-3-0348-0688-6_8

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