Molecular & Cellular Toxicology

, Volume 8, Issue 3, pp 257–262 | Cite as

Association between CD40 promoter polymorphism (rs1800686, −508 C/T) and ischemic stroke with hypertension in a Korean population

  • Jin-Man Cho
  • Bong-Keun Choe
  • Renhua Zheng
  • Jinmann Chon
  • Seung Don Yoo
  • Chong-Jin Kim
  • Geum-hee Gwak
  • Sung-Vin Yim
Original Paper

Abstract

Although glutamate toxicity is important in stroke injury, the immune and inflammatory systems are also related to stroke pathogenesis. Tumor necrosis factor (TNF) receptor superfamily member 5 (CD40) plays a crucial role in mediating a broad variety of immune and inflammatory responses. To investigate whether CD40 polymorphisms are associated with the development of ischemic stroke, two promoter single nucleotide polymorphisms (SNPs) of the CD40 gene (rs1800686, −508A/G; rs752118, −173C/T) were analyzed in 121 patients with ischemic stroke (IS) and 291 control subjects. All stroke patients were classified into clinical subgroups according to their blood pressure levels (hypertension, present and absent), fasting plasma glucose (diabetes mellitus, present and absent), and lipids (dyslipidemia, present and absent). SNPStats and SNPAnalyzer Pro software were used to obtain odds ratios (ORs), 95% confidence intervals (CIs), and Pvalues. Multiple logistic regression models (codominant1, codominant2, dominant, recessive, overdominant, and log-additive) were used to analyze the genetic data. The two tested CD40 promoter SNPs (rs1800686 and rs752118) were not associated with the development of IS, but the GT haplotype of these two SNPs was associated with the development of IS (P= 0.0148). The rs1800686 SNP frequency differed between IS patients without hypertension and those with hypertension (P=0.017, OR=0.17, 95% CI=0.04–0.72 in the codominant2 model; P=0.023, OR=0.37, 95% CI=0.15–0.90 in the dominant model; P=0.0085, OR=0.42, 95% CI=0.21–0.81 in the log-additive model; P=0.011, OR=0.47, 95% CI=0.27–0.85 in allele frequencies). The A allele frequency of rs1800686 was lower in IS patients with hypertension (27.2%) than in IS patients with hypertension (44.3%), while the G allele frequency of rs1800686 was higher in IS patients with hypertension (72.8%) than in IS patients with hypertension (55.7%). These results suggest that the GT haplotype of rs1800686 and rs752118 in the CD40 gene may be associated with the development of IS, and rs1800686 may contribute to IS in Korean patients with hypertension.

Keywords

CD40 Hypertension Ischemic stroke Pathogenesis Single nucleotide polymorphism Toxicity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Marsh, J. D. & Keyrouz, S. G. Stroke prevention and treatment. J Am Coll Cardiol 56:683–691 (2010).PubMedCrossRefGoogle Scholar
  2. 2.
    Grysiewicz, R. A., Thomas, K. & Pandey, D. K. Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin 26:871–895 (2008).PubMedCrossRefGoogle Scholar
  3. 3.
    Lanktree, M. B., Dichgans, M. & Hegele, R. A. Advances in genomic analysis of stroke: what have we learned and where are we headed? Stroke 41:825–832 (2010).PubMedCrossRefGoogle Scholar
  4. 4.
    Somarajan, B. I., Kalita, J., Mittal, B. & Misra, U. K. Evaluation of MTHFR C677T polymorphism in ischemic and hemorrhagic stroke patients. A case-control study in a Northern Indian population. J Neurol Sci 304:67–70 (2011).PubMedCrossRefGoogle Scholar
  5. 5.
    Li, X., Su, D., Zhang, X. & Zhang, C. Association of apolipoprotein A5 gene promoter region -1131T>C with risk of stroke in Han Chinese. Eur J Intern Med 22:99–102 (2011).PubMedCrossRefGoogle Scholar
  6. 6.
    Chabot, S., Charlet, D., Wilson, T. L. & Yong, V. W. Cytokine production consequent to T cell-microglia interaction: the PMA/IFN gamma-treated U937 cells display similarities to human microglia. J Neurosci Methods 105: 111–120 (2001).PubMedCrossRefGoogle Scholar
  7. 7.
    Grewal, I. S. & Flavell, R. A. CD40 and CD154 in cellmediated immunity. Annu Rev Immunol 16:111–135 (1998).PubMedCrossRefGoogle Scholar
  8. 8.
    Schumacher, H. et al. Immunophenotypic characterisation of carotid plaque: increased amount of inflammatory cells as an independent predictor for ischaemic symptoms. Eur J Vasc Endovasc Surg 21:494–501 (2001).PubMedCrossRefGoogle Scholar
  9. 9.
    Kassner, S. S. et al. The early immunological response to acute ischemic stroke: differential gene expression in subpopulations of mononuclear cells. Neuroscience 160: 394–401 (2009).PubMedCrossRefGoogle Scholar
  10. 10.
    Ishikawa, M. et al. CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion. Circulation 111:1690–1696 (2005).PubMedCrossRefGoogle Scholar
  11. 11.
    Cha, J. K. et al. Surface expression of P-selectin on platelets is related with clinical worsening in acute ischemic stroke. J Korean Med Sci 17:811–816 (2002).PubMedGoogle Scholar
  12. 12.
    Luomala, M. et al. Plasma-soluble CD40 is related to cholesterol metabolism in patients with moderate hypercholesterolemia. Scand Cardiovasc J 40:280–284 (2006).PubMedCrossRefGoogle Scholar
  13. 13.
    Lobbes, M. B. et al. Is there more than C-reactive protein and fibrinogen? The prognostic value of soluble CD40 ligand, interleukin-6 and oxidized low-density lipoprotein with respect to coronary and cerebral vascular disease. Atherosclerosis 187:18–25 (2006).PubMedCrossRefGoogle Scholar
  14. 14.
    Kim, Y. S., Yoo, J. H. & Lee, B. C. Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the Fc gamma receptor IIA. Blood Coagul Fibrinolysis 20:353–357 (2009).PubMedCrossRefGoogle Scholar
  15. 15.
    Lee, B. C. et al. Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the interleukin-1 receptor antagonist and tumor necrosis factor-alpha genes, but not the interleukin-1beta gene. Neurosci Lett 357:33–36 (2004).PubMedCrossRefGoogle Scholar
  16. 16.
    Um, J. Y. & Kim, H. M. Polymorphisms of RANTES and IL-4 genes in cerebral infarction. J Mol Neurosci 37:1–5 (2009).PubMedCrossRefGoogle Scholar
  17. 17.
    Tan, J. et al. CD40 is expressed and functional on neuronal cells. EMBO J 21:643–652 (2002).PubMedCrossRefGoogle Scholar
  18. 18.
    Inwald, D. P., McDowall, A., Peters, M. J., Callard, R. E. & Klein, N. J. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res 92:1041–1048 (2003).PubMedCrossRefGoogle Scholar
  19. 19.
    Cha, J. K. et al. Serial measurement of surface expressions of CD63, P-selectin and CD40 ligand on platelets in atherosclerotic ischemic stroke. A possible role of CD40 ligand on platelets in atherosclerotic ischemic stroke. Cerebrovasc Dis 16:376–382 (2003).PubMedCrossRefGoogle Scholar
  20. 20.
    Garlichs, C. D. et al. Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia. Stroke 34:1412–1418 (2003).PubMedCrossRefGoogle Scholar
  21. 21.
    del Rio-Espinola, A. et al. CD40-1C>T polymorphism (rs1883832) is associated with brain vessel reocclusion after fibrinolysis in ischemic stroke. Pharmacogenomics 11:763–772 (2010).PubMedCrossRefGoogle Scholar
  22. 22.
    Wang, M., Li, Y., Li, W., Xia, Z. E. & Wu, Q. The CD40 gene polymorphism rs1883832 is associated with risk of acute coronary syndrome in a Chinese case-control study. DNA Cell Biol 30:173–178 (2011).PubMedCrossRefGoogle Scholar
  23. 23.
    Rodriguez-Rodriguez, L. et al. Influence of CD40 rs1883832 polymorphism in susceptibility to and clinical manifestations of biopsy-proven giant cell arteritis. J Rheumatol 37:2076–2080 (2010).PubMedCrossRefGoogle Scholar
  24. 24.
    Pineda, B. et al. Gene-gene interaction between CD40 and CD40L reduces bone mineral density and increases osteoporosis risk in women. Osteoporos Int 22:1451–1458 (2010).PubMedCrossRefGoogle Scholar
  25. 25.
    Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 40:1216–1223 (2008).PubMedCrossRefGoogle Scholar
  26. 26.
    Skibola, C. F. et al. A functional TNFRSF5 gene variant is associated with risk of lymphoma. Blood 111:4348–4354 (2008).PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society of Toxicogenomics and Toxicoproteomics and Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Jin-Man Cho
    • 1
  • Bong-Keun Choe
    • 2
  • Renhua Zheng
    • 3
  • Jinmann Chon
    • 4
  • Seung Don Yoo
    • 4
  • Chong-Jin Kim
    • 1
  • Geum-hee Gwak
    • 5
  • Sung-Vin Yim
    • 2
    • 3
  1. 1.Division of Cardiology, Department of Internal Medicine, School of MedicineKyung Hee UniversitySeoulKorea
  2. 2.Kohwang Medical Research InstituteKyung Hee UniversitySeoulKorea
  3. 3.Department of Clinical Pharmacology, School of MedicineKyung Hee UniversitySeoulKorea
  4. 4.Department of Physical Medicine & Rehabilitation, School of MedicineKyung Hee UniversitySeoulKorea
  5. 5.Department of Biochemistry and Molecular Biology, School of MedicineKyung Hee UniversitySeoulKorea

Personalised recommendations