Inflammation Research

, Volume 61, Issue 3, pp 177–188 | Cite as

TLR4 polymorphisms and disease susceptibility

  • Mamoona Noreen
  • Muhammad Ali A. Shah
  • Sheeba Murad Mall
  • Shazia Choudhary
  • Tahir Hussain
  • Iltaf Ahmed
  • Syed Fazal Jalil
  • Muhammad Imran Raza


Toll-like receptors (TLRs) play a central role in the regulation of the host immune system. Each TLR recognizes specific pathogen-associated molecular patterns (PAMPs). TLR4 is one of the well characterized pathogen recognition receptors (PRRs) that recognizes the lipopolysaccharide (LPS) of Gram-negative bacteria, some conserved structures from fungal to mycobacterial pathogens and some endogenous ligands. A complex signaling cascade initiates after the ligand binds to the TLR4 ectodomain, leading to the activation of multiple inflammatory genes. Genetic variations greatly influence immune responses towards pathogenic challenges and disease outcome. In this review, we summarize various reports regarding TLR4 polymorphisms and disease susceptibility.


Immunity Infection TLR4 Polymorphism Susceptibility Disease 


  1. 1.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83.PubMedCrossRefGoogle Scholar
  2. 2.
    Beutler B. Innate immunity: an overview. Mol Immunol. 2004;40:845–59.PubMedCrossRefGoogle Scholar
  3. 3.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Lemaitre B. The road to Toll. Nature Rev Immunol. 2004;4:521–7.CrossRefGoogle Scholar
  5. 5.
    Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA. 2004;101:3516–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Miggin SM, O’Neill LA. New insights into the regulation of TLR signaling. J Leukoc Biol. 2006;80:220–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. Toll-like receptors control activation of adaptive immune responses. Nature Immunol. 2001;2:947–50.CrossRefGoogle Scholar
  9. 9.
    Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol. 2004;4:499–511.PubMedCrossRefGoogle Scholar
  10. 10.
    Akira S, Yamamoto M, Takeda K. Role of adapters in Toll-like receptor signaling. Biochem Soc Trans. 2003;31(Pt. 3):637–42.PubMedGoogle Scholar
  11. 11.
    Vogel SN, Fitzgerald KA, Fenton MJ. TLRs: differential adapter utilization by Toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv. 2003;3:466–77.PubMedCrossRefGoogle Scholar
  12. 12.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in TLR4 gene. Science. 1998;282:2085–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the LPS gene product. J Immunol. 1999;162:3749–52.PubMedGoogle Scholar
  14. 14.
    Ohashi K, Burkart V, Flohe S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000;164:558–61.PubMedGoogle Scholar
  15. 15.
    Roelofs MF, Boelens WC, Joosten LA, Abdollahi-Roodsaz S, Geurts J, Wunderink LU, et al. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J Immunol. 2006;176:7021–7.PubMedGoogle Scholar
  16. 16.
    Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol. 2002;3:667–72.PubMedGoogle Scholar
  17. 17.
    Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005;6:565–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Jack RS, Fan X, Bernheiden M, Rune G, Ehlers M, Weber A, et al. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature. 1997;389:742–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Lye E, Mirtsos C, Suzuki N, Suzuki S, Yeh WC. The role of interleukin 1 receptor associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem. 2004;279:40653–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin dependent kinase of MKK and IKK. Nature. 2001;412:346–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X. IRAK-mediated translocation of TRAF6 and TAB 2 in the interleukin-1-induced activation of NFkappa B. J Biol Chem. 2001;276:41661–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X. Interleukin-1 (IL-1) receptor associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB 2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol. 2002;22:7158–67.PubMedCrossRefGoogle Scholar
  23. 23.
    Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, et al. Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem. 2003;278:26258–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Doyle SL, Jefferies CA, O’Neill LA. Bruton’s tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkappaB activation by lipopolysaccharide. J Biol Chem. 2005;280:23496–501.PubMedCrossRefGoogle Scholar
  25. 25.
    Gray P, Dunne A, Brikos C, Jefferies CA, Doyle SL, O’Neill LA. MyD88 adapter-like (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction. J Biol Chem. 2006;281:10489–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, et al. LPS TLR4 signaling to IRF-3/7 and NF-KB involves the Toll adapters TRAM and TRIF. J Exp Med. 2003;198:1043–55.PubMedCrossRefGoogle Scholar
  27. 27.
    Jiang Z, Zamanian-Daryoush M, Nie H, Silva AM, Williams BR, Li X. Poly(I-C)-induced Toll-like receptor 3 (TLR3)- mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB 2-PKR. J Biol Chem. 2003;278:16713–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Jiang Z, Mak TW, Sen G, Li X. Toll-like receptor 3-mediated activation of NF kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proc Natl Acad Sci USA. 2004;101:3533–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, et al. RIP1 is an essential mediator of Toll like receptor 3 induced NF-kappa B activation. Nat Immunol. 2004;5:503–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor 3, in the Toll-like receptor signaling. J Immunol. 2003;171:4304–10.PubMedGoogle Scholar
  31. 31.
    Hill AV. The genomics and genetics of human infectious disease susceptibility. Annu Rev Genomics Hum Genet. 2001;2:373–400.PubMedCrossRefGoogle Scholar
  32. 32.
    Notarangelo L, Casanova JL, Conley ME, Chapel H, Fischer A, Puck J, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol. 2006;117:883–96.PubMedCrossRefGoogle Scholar
  33. 33.
    Schroder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005;5:156–64.PubMedGoogle Scholar
  34. 34.
    Orange JS, Geha RS. Finding NEMO: genetic disorders of NF-κB activation. J Clin Invest. 2003;112:983–5.PubMedGoogle Scholar
  35. 35.
    Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-κB-mediated immunity in man. Curr Opin Immunol. 2004;16:34–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B. Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus (TLR4). Genome Biol. 2000;1:R002.CrossRefGoogle Scholar
  37. 37.
    Smirnova I, Hamblin MT, McBride C, Beutler B, Di Rienzo A. Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans. Genetics. 2001;158:1657–64.PubMedGoogle Scholar
  38. 38.
    Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci USA. 2003;100:6075–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Hawn TR, Verbon A, Janer M, Zhao LP, Beutler B, Aderem A. Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc Natl Acad Sci USA. 2005;102:2487–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Michel O, LeVan TD, Stern D, Dentener M, Thorn J, Gnat D, et al. Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Clin Immunol. 2003;112:923–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Fageras Bottcher M, Hmani-Aifa M, Lindstrom A, Jenmalm MC, Mai XM, Nilsson L, et al. A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol. 2004;114:561–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Erridge C, Stewart J, Poxton IR. Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the Toll-like receptor 4 gene show no deficit in lipopolysaccharide signalling. J Exp Med. 2003;197:1787–91.PubMedCrossRefGoogle Scholar
  44. 44.
    von Aulock S, Schroder NW, Gueinzius K, Traub S, Hoffmann S, Graf K, et al. Heterozygous toll-like receptor 4 polymorphism does not influence lipopolysaccharide-induced cytokine release in human whole blood. J Infect Dis. 2003;188:938–43.CrossRefGoogle Scholar
  45. 45.
    Schippers EF, van‘t Veer C, van Voorden S, Martina CA, Huizinga TW, le Cessie S, et al. IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine. 2005;29:215–228.Google Scholar
  46. 46.
    van der Graaf C, Kullberg BJ, Joosten L, Verver-Jansen T, Jacobs L, Van der Meer JW, et al. Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism. Cytokine. 2005;30:264–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Paulus SC, Hirschfeld AF, Victor RE, Brunstein J, Thomas E, Turvey SE. Common human Toll-like receptor 4 polymorphisms-Role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin Immunol. 2007;123:252–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Calvano JE, owers DJ, Coyle SM, Macor M, Reddell MT, Kumar A, et al. Response to systemic endotoxemia among humans bearing polymorphisms of the Toll-like receptor 4 (hTLR4). Clin Immunol. 2006;121:186–90.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007;130:906–17.PubMedCrossRefGoogle Scholar
  50. 50.
    Rallabhandi P, Bell J, Boukhvalova MS, Medvedev A, Lorenz E, Arditi M, et al. Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J Immunol. 2006;177:322–32.PubMedGoogle Scholar
  51. 51.
    Read RC, Pullin J, Gregory S, Borrow R, Kaczmarski EB, di Giovine FS, et al. A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis. 2001;184:640–2.PubMedCrossRefGoogle Scholar
  52. 52.
    Allen A, Obaro S, Bojang K, Awomoyi AA, Greenwood BM, Whittle H, et al. Variation in Toll-like receptor 4 and susceptibility to group A meningococcal meningitis in Gambian children. Pediatr Infect Dis J. 2003;22:1018–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Faber J, Meyer CU, Gemmer C, Russo A, Finn A, Murdoch C, et al. Human toll-like receptor 4 mutations are associated with susceptibility to invasive meningococcal disease in infancy. Pediatr Infect Dis J. 2006;25:80–1.PubMedCrossRefGoogle Scholar
  54. 54.
    Karoly E, Fekete A, Banki NF, Szebeni B, Vannay A, Szabo AJ, et al. Heatshock protein 72 (HSPA1B) gene polymorphism and Toll-like receptor (TLR) 4 mutation are associated with increased risk of urinary tract infection in children. Pediatr Res. 2007;61:371–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Cooke GS, Segal S, Hill AV. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002;347:1978–80.PubMedCrossRefGoogle Scholar
  56. 56.
    Newport MJ, Allen A, Awomoyi AA, Dunstan SJ, McKinney E, Marchant A, et al. The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis. 2004;84:347–52.PubMedCrossRefGoogle Scholar
  57. 57.
    Ferwerda B, Kibiki GS, Netea MG, Dolmans WM, van der Ven AJ. The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania. AIDS. 2007;21:1375–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Moens L, Verhaegen J, Pierik M, Vermeire S, De Boeck K, Peetermans WE, et al. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in invasive pneumococcal disease. Microbes Infect. 2007;9:15–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Barber RC, Chang LY, Arnoldo BD, Purdue GF, Hunt JL, Horton JW, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res. 2006;4:250–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Child NJ, Yang IA, Pulletz MC, de Courcy-Golder K, Andrews AL, Pappachan VJ, et al. Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome. Biochem Soc Trans. 2003;31:652–3.PubMedCrossRefGoogle Scholar
  61. 61.
    Feterowski C, Emmanuilidis K, Miethke T, Gerauer K, Rump M, Ulm K, et al. Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Immunology. 2003;109:426–31.PubMedCrossRefGoogle Scholar
  62. 62.
    Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis. 2002;186:1522–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med. 2002;162:1028–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000;1:398–401.PubMedCrossRefGoogle Scholar
  65. 65.
    Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol. 2001;75:10730–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Gagro A, Tominac M, Krsulovic-Hresic V, Bace A, Matic M, Drazenovic V, et al. Increased Toll-like receptor 4 expression in infants with respiratory syncytial virus bronchiolitis. Clin Exp Immunol. 2004;135:267–72.PubMedCrossRefGoogle Scholar
  67. 67.
    Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E, Tal A, et al. Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J Infect Dis. 2004;189:2057–63.PubMedCrossRefGoogle Scholar
  68. 68.
    Mandelberg A, Tal G, Naugolny L, Cesar K, Oron A, Houri S, et al. Lipopolysaccharide hyporesponsiveness as a risk factor for intensive care unit hospitalization in infants with respiratory syncytial virus bronchiolitis. Clin Exp Immunol. 2006;144:48–52.PubMedCrossRefGoogle Scholar
  69. 69.
    Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB, Boukhvalova MS, et al. Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J Immunol. 2007;179:3171–7.PubMedGoogle Scholar
  70. 70.
    Lofgren J, Marttila R, Renko M, Ramet M, Hallman M. Toll-like receptor 4 Asp299Gly polymorphism in respiratory syncytial virus epidemics. Pediatr Pulmonol. 2010;45:687–92.PubMedCrossRefGoogle Scholar
  71. 71.
    Kesh S, Mensah NY, Peterlongo P, Jaffe D, Hsu K, van den Brink M, et al. TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann N Y Acad Sci. 2005;1062:95–103.PubMedCrossRefGoogle Scholar
  72. 72.
    Morre SA, Murillo LS, Spaargaren J, Fennema HS, Pena AS. Role of the toll-like receptor 4 Asp299Gly polymorphism in susceptibility to Candida albicans infection. J Infect Dis. 2002;186:1377–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Van der Graaf CA, Netea MG, Morre SA, Den Heijer M, Verweij PE, Van der Meer JW, et al. Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw. 2006;17:29–34.PubMedGoogle Scholar
  74. 74.
    Rezazadeh M, Hajilooi M, Rafiei A, Haidari M, Nikoopour E, Kerammat F, et al. TLR4 polymorphism in Iranian patients with brucellosis. J Infect. 2006;53:206–10.PubMedCrossRefGoogle Scholar
  75. 75.
    Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, et al. Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci USA. 2006;103:177–82.PubMedCrossRefGoogle Scholar
  76. 76.
    Mockenhaupt FP, Hamann L, von Gaertner C, Bedu-Addo G, von Kleinsorgen C, Schumann RR, et al. Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis. 2006;194:184–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Schmausser B, Andrulis M, Endrich S, Lee SK, Josenhans C, Muller-Hermelink HK, et al. Expression and subcellular distribution of Toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol. 2004;136:521–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Kato I, Canzian F, Plummer M, Franceschi S, van Doorn LJ, Vivas J, et al. Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signalling and gastric precancerous lesions in a population at high risk for gastric cancer. Dig Dis Sci. 2007;52:254–61.PubMedCrossRefGoogle Scholar
  79. 79.
    Hold GL, Rabkin CS, Chow WH, Smith MG, Gammon MD, Risch HA, et al. A functional polymorphism of Toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology. 2007;132:905–12.PubMedCrossRefGoogle Scholar
  80. 80.
    Achyut BR, Ghoshal UC, Moorchung N, Mittal B. Association of Toll-like receptor-4 (Asp299Gly and Thr399Ileu) gene polymorphisms with gastritis and precancerous lesions. Hum Immunol. 2007;68:901–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Rigoli L, Bella DI C, Fedele F, Procopio V, Amorini M, et al. TLR4 and NOD2/CARD15 genetic polymorphisms and their possible role in gastric carcinogenesis. Anticancer Res. 2010;30:513–7.PubMedGoogle Scholar
  82. 82.
    Trejo-de la OA, Torres J, Pérez-Rodriguez M, Camorlinga-Ponce M, Luna LF, Abdo-Francis JM, et al. TLR4 single-nucleotide polymorphisms alter mucosal cytokine and chemokine patterns in Mexican patients with Helicobacter pylori-associated gastroduodenal diseases. Clin Immunol. 2008;129:333–40.CrossRefGoogle Scholar
  83. 83.
    Garza-Gonzalez E, Bosques-Padilla FJ, Mendoza-Ibarra SI, Flores-Gutierrez JP, Maldonado-Garza HJ, Perez–Perez GI. Assessment of the Toll-like receptor 4 Asp299Gly, Thr399Ile and interleukin-8–251 polymorphisms in the risk for the development of distal gastric cancer. BMC Cancer. 2007;7:70.PubMedCrossRefGoogle Scholar
  84. 84.
    Santini D, Angeletti S, Ruzzo A, Dicuonzo G, Galluzzo S, Vincenzi B, et al. Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in gastric cancer of intestinal and diffuse histotypes. Clin Exp Immunol. 2008;154:360–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Hishida A, Matsuo K, Goto Y, Mitsuda Y, Hiraki A, Naito M, et al. Toll-like receptor 4 +3725G/C polymorphism, Helicobacter pylori seropositivity, and the risk of gastric atrophy and gastric cancer in Japanese. Helicobacter. 2009;14:47–53.PubMedCrossRefGoogle Scholar
  86. 86.
    Chen YC, Giovannucci E, Lazarus R, Kraft P, Ketkar S, Hunter DJ. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res. 2005;65:11771–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Cheng I, Plummer SJ, Casey G, Witte JS. Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2007;16:352–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Zheng SL, Augustsson-BAlter K, Chang B, Hedelin M, Li L, Adami HO, et al. Sequence variants of Toll-like receptor 4 are associated with prostate cancer risk: results from the cancer prostate in Sweden study. Cancer Res. 2004;64:2918–22.PubMedCrossRefGoogle Scholar
  89. 89.
    Balistreri CR, Caruso C, Carruba G, Miceli V, Campisi I, ListÍ F, et al. A pilot study on prostate cancer risk and pro-inflammatory genotypes: pathophysiology and therapeutic implications. Curr Pharm Des. 2010;16:718–24.PubMedCrossRefGoogle Scholar
  90. 90.
    Wang MH, Helzlsouer KJ, Smith MW, Hoffman-Bolton JA, Clipp SL, Grinberg V, et al. Association of IL10 and other immune response- and obesity-related genes with prostate cancer in CLUE II. Prostate. 2009;69:874–85.PubMedCrossRefGoogle Scholar
  91. 91.
    Boraska Jelavic T, Barisic M, Drmic Hofman I, Boraska V, Vrdoljak E, Peruzovic M, et al. Polymorphism in the Toll-like receptor 2 is associated with colorectal cancer. Clin Genet. 2006;70:156–60.PubMedCrossRefGoogle Scholar
  92. 92.
    Landi S, Gemignani F, Bottari F, Gioia-Patricola L, Guino E, Cambray M, et al. Polymorphisms within inflammatory genes and colorectal cancer. J Negat Results Biomed. 2006;5:15.Google Scholar
  93. 93.
    Pandey S, Mittal RD, Srivastava M, Srivastava K, Singh S, Srivastava S, Mittal B. Impact of Toll-like receptors [TLR] 2 (–196 to –174 del) and TLR 4 (Asp299Gly, Thr399Ile) in cervical cancer susceptibility in North Indian women. Gynecol Oncol. 2009;114:501–5.PubMedCrossRefGoogle Scholar
  94. 94.
    Mori Y, Yoshimura A, Ukai T, Lien E, Espevik T, Hara Y. Immunohistochemical localization of Toll-like receptors 2 and 4 in gingival tissue from patients with periodontitis. Oral Microbiol Immunol. 2003;18:54–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Ren L, Leung WK, Darveau RP, Jin L. The expression profile of lipopolysaccharide-binding protein, membrane-bound CD14, and toll-like receptors 2 and 4 in chronic periodontitis. J Periodontol. 2005;76:1950–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Wang PL, Ohura K, Fujii T, Oido-Mori M, Kowashi Y, Kikuchi M, et al. DNA microarray analysis of human gingival fibroblasts from healthy and inflammatory gingival tissues. Biochem Biophys Res Commun. 2003;305:970–3.PubMedCrossRefGoogle Scholar
  97. 97.
    Kinane DF, Peterson M, Stathopoulou PG. Environmental and other modifying factors of the periodontal diseases. Periodontol 2000. 2006;40:107–119.Google Scholar
  98. 98.
    Kinane DF, Shiba H, Stathopoulou PG, Zhao H, Lappin DF, Singh A, et al. Gingival epithelial cells heterozygous for Toll-like receptor 4 polymorphisms Asp299Gly and Thr399ile are hypo-responsive to Porphyromonas gingivalis. Genes Immun. 2006;7:190–200.PubMedCrossRefGoogle Scholar
  99. 99.
    Ozturk A, Vieira AR. TLR4 as a risk factor for periodontal disease: a reappraisal. J Clin Periodontol. 2009;36:279–86.PubMedCrossRefGoogle Scholar
  100. 100.
    Michelsen KS, Doherty TM, Shah PK, Arditi M. TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol. 2004;173:5901–7.PubMedGoogle Scholar
  101. 101.
    Michelsen KS, Doherty TM, Shah PK, Arditi M. Role of Toll-like receptors in atherosclerosis. Circ Res. 2004;95:e96–7.PubMedGoogle Scholar
  102. 102.
    Kalayoglu MV, Libby P, Byrne GI. Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA. 2002;288:2724–31.PubMedCrossRefGoogle Scholar
  103. 103.
    Lehr HA, Sagban TA, Ihling C, Zahringer U, Hungerer KD, Blumrich M, et al. Immunopathogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet. Circulation. 2001;104:914–20.PubMedCrossRefGoogle Scholar
  104. 104.
    Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001;104:3103–8.PubMedCrossRefGoogle Scholar
  105. 105.
    Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002;347:185–92.PubMedCrossRefGoogle Scholar
  106. 106.
    Ameziane N, Beillat T, Verpillat P, Chollet-Martin S, Aumont MC, Seknadji P, et al. Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol. 2003;23:e61–4.PubMedCrossRefGoogle Scholar
  107. 107.
    Balistreri CR, Candore G, Colonna-Romano G, Lio D, Caruso M, Hoffmann E, et al. Role of Toll like receptor 4 in acute myocardial infarction and longevity. JAMA. 2004;292:2339–40.PubMedCrossRefGoogle Scholar
  108. 108.
    Yang IA, Holloway JW, Ye S. TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis. Atherosclerosis. 2003;170:187–90.PubMedCrossRefGoogle Scholar
  109. 109.
    Reismann P, Lichy C, Rudofsky G, Humpert PM, Genius J, Si TD, et al. Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia. J Neurol. 2004;251:853–8.PubMedGoogle Scholar
  110. 110.
    Edfeldt K, Bennet AM, Eriksson P, Frostegard J, Wiman B, Hamsten A, et al. Association of hyporesponsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J. 2004;25:1447–53.PubMedCrossRefGoogle Scholar
  111. 111.
    Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA. Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res. 2002;52:373–6.PubMedGoogle Scholar
  112. 112.
    Torok HP, Glas J, Tonenchi L, Mussack T, Folwaczny C. Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. Clin Immunol. 2004;112:85–91.PubMedCrossRefGoogle Scholar
  113. 113.
    Yang IA, Barton SJ, Rorke S, Cakebread JA, Keith TP, Clough JB, et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun. 2004;5:41–5.PubMedCrossRefGoogle Scholar
  114. 114.
    Radstake TR, Franke B, Hanssen S, Netea MG, Welsing P, Barrera P, et al. The Toll-like receptor 4 Asp299Gly functional variant is associated with decreased rheumatoid arthritis disease susceptibility but does not influence disease severity and/or outcome. Arthritis Rheum. 2004;50:999–1001.PubMedCrossRefGoogle Scholar
  115. 115.
    Rudofsky G Jr, Reismann P, Witte S, Humpert PM, Isermann B, Chavakis T, et al. Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes. Diabetes Care. 2004;27:179–83.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Mamoona Noreen
    • 1
  • Muhammad Ali A. Shah
    • 1
  • Sheeba Murad Mall
    • 1
  • Shazia Choudhary
    • 1
  • Tahir Hussain
    • 1
  • Iltaf Ahmed
    • 1
  • Syed Fazal Jalil
    • 1
  • Muhammad Imran Raza
    • 1
  1. 1.NUST Centre of Virology and Immunology (NCVI)National University of Sciences and Technology (NUST)IslamabadPakistan

Personalised recommendations