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Association of Toll-like Receptor 2 Polymorphisms with National Institute of Health Stroke Scale Scores of Ischemic Stroke Patients

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Abstract

Toll-like receptor 2 (TLR2) has been shown to have an important role in the postischemic inflammatory response and to contribute to ischemic brain damage. In this study, we investigated whether coding region single nucleotide polymorphisms (SNPs) of the TLR2 gene were associated with ischemic stroke (IS) and with clinical phenotypes in IS patients. We genotyped two SNPs (rs3804099 [Asn199Asn] and rs3804100 [Ser450Ser]) using direct sequencing in 202 IS patients and 291 control subjects. No SNPs of the TLR2 gene were found to be associated with IS. However, in analysis of clinical phenotypes, we found that rs3804099 was associated with the National Institute of Health Stroke Scale (NIHSS) scores of IS patients in codominant (TC vs. TT, p = 0.0005; CC vs. TT, p = 0.0007) and dominant models (TC/CC vs. TT, p = 0.0001). Also, rs3804100 revealed significant association in codominant (TC vs. TT, p = 0.0002; CC vs. TT, p = 0.008) and dominant models (TC/CC vs. TT, p < 0.0001). In allele frequency analysis, we also found that the C alleles of rs3804099 and rs3804100 were associated with higher NIHSS scores (p = 0.0003 in rs3804099; p = 0.0001 in rs3804100). Our results suggest that TLR2 may be related to severe IS.

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References

  • Aderem A, Ulevitch RJ (2000) Toll-like receptors in the induction of the innate immune response. Nature 406:782–787

    Article  PubMed  CAS  Google Scholar 

  • Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680

    Article  PubMed  CAS  Google Scholar 

  • Anderson KV (2000) Toll signaling pathways in the innate immune response. Curr Opin Immunol 12:13–19

    Article  PubMed  CAS  Google Scholar 

  • Babcock AA, Wirenfeldt M, Holm T et al (2006) Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation. J Neurosci 49:12826–12837

    Article  Google Scholar 

  • Brea D, Blanco M, Ramos-Cabrer P et al (2011) Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values. J Cereb Blood Flow Metab 31:1424–1431

    Article  PubMed  CAS  Google Scholar 

  • Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I (2008) Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and the worsening of experimental stroke. Stroke 39:1314–1320

    Article  PubMed  CAS  Google Scholar 

  • Chen KH, Gu W, Zeng L et al (2011) Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock 35:35–41

    Article  PubMed  Google Scholar 

  • Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127–136

    PubMed  CAS  Google Scholar 

  • Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623

    Article  PubMed  CAS  Google Scholar 

  • Durukan A, Tatlisumak T (2007) Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 87:179–197

    Article  PubMed  CAS  Google Scholar 

  • Enquobahrie DA, Smith NL, Bis JC et al (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 101:1683–1688

    Article  PubMed  CAS  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H et al (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  PubMed  CAS  Google Scholar 

  • Jiang C, Wang J, Li X, Liu C, Chen N, Hao Y (2009) Progesterone exerts neuroprotective effects by inhibiting inflammatory response after stroke. Inflamm Res 58:619–624

    Article  PubMed  CAS  Google Scholar 

  • Lalouschek W, Schillinger M, Hsieh K et al (2006) Polymorphisms of the inflammatory system and risk of ischemic cerebrovascular events. Clin Chem Lab Med 44:918–923

    Article  PubMed  CAS  Google Scholar 

  • 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 180:305–309

    Article  PubMed  CAS  Google Scholar 

  • Liu T, Clark RK, McDonnell PC et al (1994) Tumor necrosis factor-α expression in ischemic neurons. Stroke 25:1481–1488

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Rädler D, Illi S et al (2011) TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy. Allergy 66:1020–1029

    Article  PubMed  CAS  Google Scholar 

  • Nijboer CH, Heijnen CJ, Groenendaal F, May MJ, van Bel F, Kavelaars A (2008) Strong neuroprotection by inhibition of NF-κB after neonatal hypoxia–ischemia involves apoptotic mechanisms but is independent of cytokines. Stroke 39:2129–2137

    Article  PubMed  CAS  Google Scholar 

  • O'Donnell MJ, Xavier D, Liu L et al (2010) Risk factors for ischaemic and intracerebral hemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376:112–123

    Article  PubMed  Google Scholar 

  • Reismann P, Lichy C, Rudofsky G et al (2004) Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia. J Neurol 251:853–858

    PubMed  CAS  Google Scholar 

  • Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9:429–439

    Article  PubMed  CAS  Google Scholar 

  • Seegers H, Grillon E, Trioullier Y, Väth A, Verna JM, Blum D (2000) Nuclear factor-κB activation in permanent intraluminal focal cerebral ischemia in the rat. Neurosci Lett 288:241–245

    Article  PubMed  CAS  Google Scholar 

  • Tang S, Arumugam T, Xu X et al (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 104:13798–13803

    Article  PubMed  CAS  Google Scholar 

  • Urra X, Cervera A, Obach V, Climent N, Planas AM, Chamorro A (2009) Monocytes are major players in the prognosis and risk of infection after acute stroke. Stroke 40:1262–1268

    Article  PubMed  CAS  Google Scholar 

  • Weng WC, Huang WY, Chien YY et al (2011) The impact of smoking on the severity of acute ischemic stroke. J Neurol Sci. doi:10.1016/j.jns.2011.05.046

  • Yang QW, Li JC, Lu FL et al (2008) Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. J Cereb Blood Flow Metab 28:1588–1596

    Article  PubMed  CAS  Google Scholar 

  • Ziegler G, Freyer D, Harhausen D, Khojasteh U, Nietfeld W, Trendelenburg G (2011) Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke. J Cereb Blood Flow Metab 31:757–766

    Article  PubMed  CAS  Google Scholar 

  • Ziegler G, Harhausen D, Schepers C et al (2007) TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 359:574–579

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Kyung Hee University in 2011 (KHU- 20110061).

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Correspondence to Joo-Ho Chung.

Electronic Supplementary Material

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Supplementary Table 1

Sequences of the primers used for each SNP in Toll-like receptor 2 gene (DOCX 13 kb)

Supplementary Table 2

Multiple logistic regression analysis of Toll-like receptor 2 gene polymorphisms in ischemic stroke patients and control subjects (DOCX 16 kb)

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Park, H.J., Kim, S.K., Yun, D.H. et al. Association of Toll-like Receptor 2 Polymorphisms with National Institute of Health Stroke Scale Scores of Ischemic Stroke Patients. J Mol Neurosci 46, 536–540 (2012). https://doi.org/10.1007/s12031-011-9640-1

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