Skip to main content

Advertisement

Log in

Novel CD137 Gene Polymorphisms and Susceptibility to Ischemic Stroke in the Northern Chinese Han Population

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Ischemic stroke is a leading cause of mortality and morbidity worldwide, and atherosclerosis is one of the major risk factors for this neurologic deficit. Recent studies have revealed the important role of CD137 in human atherosclerosis. Here, we analyzed the association of CD137 single nucleotide polymorphisms (SNPs) with ischemic stroke. We assessed three SNPs (rs161827, rs161818, and rs161810) of the CD137 gene and their association with ischemic stroke in a northern Chinese Han population. A total of 496 ischemic stroke patients and 486 gender-matched control subjects were genotyped. We classified these patients according to complications with diabetes and hypertension and also by ischemic stroke subtypes. Allele, genotype, and haplotype association studies were tested in all patients and subgroups. We used multivariable logistic regression analysis combined with 10,000 permutations to analyze the association of CD137 polymorphisms with ischemic stroke. After adjusting for relevant factors, rs161827 was significantly different between patients with and without diabetes and the control group (p = 0.0001, p = 0.014, and p = 0.0001, respectively). In addition, rs161818 and rs161810 differed significantly between patients without diabetes and the control subjects (p = 0.0001 and p = 0.004, respectively). rs161827, rs161818, and rs161810 were all statistically significant among the combination stroke subgroup compared with the controls. These results indicate that the CD137 gene is associated with risk of ischemic stroke in the northern Han Chinese. Moreover, CD137 gene polymorphism may be one mediating factor between diabetes and ischemic stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adams, H. P., Jr., Bendixen, B. H., Kappelle, L. J., Biller, J., Love, B. B., Gordon, D. L., et al. (1993). Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 24(1), 35–41.

    Article  PubMed  Google Scholar 

  • Amarenco, P., Cohen, A., Tzourio, C., Bertrand, B., Hommel, M., Besson, G., et al. (1994). Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. New England Journal of Medicine, 331(22), 1474–1479. doi:10.1056/nejm199412013312202.

    Article  CAS  PubMed  Google Scholar 

  • Arch, R. H., & Thompson, C. B. (1998). 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Molecular and Cellular Biology, 18(1), 558–565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Croft, M. (2003). Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nature Reviews Immunology, 3(8), 609–620. doi:10.1038/nri1148.

    Article  CAS  PubMed  Google Scholar 

  • Dang, M., Wang, Z., Zhang, R., Li, X., Peng, Y., Han, X., et al. (2015). KALRN rare and common variants and susceptibility to ischemic stroke in Chinese Han population. Neuromolecular Medicine, 17(3), 241–250. doi:10.1007/s12017-015-8352-z.

    Article  CAS  PubMed  Google Scholar 

  • Feigin, V. L., Lawes, C. M., Bennett, D. A., & Anderson, C. S. (2003). Stroke epidemiology: A review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurology, 2(1), 43–53.

    Article  PubMed  Google Scholar 

  • Guilherme, A., Virbasius, J. V., Puri, V., & Czech, M. P. (2008). Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nature Reviews Molecular Cell Biology, 9(5), 367–377. doi:10.1038/nrm2391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haga, T., Suzuki, J., Kosuge, H., Ogawa, M., Saiki, H., Haraguchi, G., et al. (2009). Attenuation of experimental autoimmune myocarditis by blocking T cell activation through 4-1BB pathway. Journal of Molecular and Cellular Cardiology, 46(5), 719–727. doi:10.1016/j.yjmcc.2009.02.003.

    Article  CAS  PubMed  Google Scholar 

  • Hansson, G. K. (2005). Inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine, 352(16), 1685–1695. doi:10.1056/NEJMra043430.

    Article  CAS  PubMed  Google Scholar 

  • Hassan, A., & Markus, H. S. (2000). Genetics and ischaemic stroke. Brain, 123(Pt 9), 1784–1812.

    Article  PubMed  Google Scholar 

  • Irie, J., Wu, Y., Kachapati, K., Mittler, R. S., & Ridgway, W. M. (2007). Modulating protective and pathogenic CD4+subsets via CD137 in type 1 diabetes. Diabetes, 56(1), 186–196. doi:10.2337/db06-0793.

    Article  CAS  PubMed  Google Scholar 

  • Jeon, H. J., Choi, J. H., Jung, I. H., Park, J. G., Lee, M. R., Lee, M. N., et al. (2010). CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation, 121(9), 1124–1133. doi:10.1161/circulationaha.109.882704.

    Article  CAS  PubMed  Google Scholar 

  • Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., et al. (1996). Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 383(6602), 707–710. doi:10.1038/383707a0.

    Article  CAS  PubMed  Google Scholar 

  • Jung, I. H., Choi, J. H., Jin, J., Jeong, S. J., Jeon, S., Lim, C., et al. (2014). CD137-inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice. Faseb Journal, 28(11), 4779–4791. doi:10.1096/fj.14-253732.

    Article  CAS  PubMed  Google Scholar 

  • Kim, C. S., Kim, J. G., Lee, B. J., Choi, M. S., Choi, H. S., Kawada, T., et al. (2011). Deficiency for costimulatory receptor 4-1BB protects against obesity-induced inflammation and metabolic disorders. Diabetes, 60(12), 3159–3168. doi:10.2337/db10-1805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klingenberg, R., Gerdes, N., Badeau, R. M., Gistera, A., Strodthoff, D., Ketelhuth, D. F., et al. (2013). Depletion of FOXP3+regulatory T cells promotes hypercholesterolemia and atherosclerosis. Journal of Clinical Investigation, 123(3), 1323–1334. doi:10.1172/jci63891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon, B. (2009). CD137–CD137 Ligand Interactions in Inflammation. Immune Network, 9(3), 84–89. doi:10.4110/in.2009.9.3.84.

    Article  PubMed  PubMed Central  Google Scholar 

  • Legein, B., Temmerman, L., Biessen, E. A., & Lutgens, E. (2013). Inflammation and immune system interactions in atherosclerosis. Cellular and Molecular Life Sciences, 70(20), 3847–3869. doi:10.1007/s00018-013-1289-1.

    Article  CAS  PubMed  Google Scholar 

  • Libby, P., Ridker, P. M., & Hansson, G. K. (2011). Progress and challenges in translating the biology of atherosclerosis. Nature, 473(7347), 317–325. doi:10.1038/nature10146.

    Article  CAS  PubMed  Google Scholar 

  • Lo, J. C., Wang, Y., Tumanov, A. V., Bamji, M., Yao, Z., Reardon, C. A., et al. (2007). Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science, 316(5822), 285–288. doi:10.1126/science.1137221.

    Article  CAS  PubMed  Google Scholar 

  • Olofsson, P. S., Soderstrom, L. A., Wagsater, D., Sheikine, Y., Ocaya, P., Lang, F., et al. (2008). CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation, 117(10), 1292–1301. doi:10.1161/circulationaha.107.699173.

    Article  CAS  PubMed  Google Scholar 

  • Ria, M., Eriksson, P., Boquist, S., Ericsson, C. G., Hamsten, A., & Lagercrantz, J. (2006). Human genetic evidence that OX40 is implicated in myocardial infarction. Biochemical and Biophysical Research Communications, 339(3), 1001–1006. doi:10.1016/j.bbrc.2005.11.092.

    Article  CAS  PubMed  Google Scholar 

  • Sabbagh, L., Pulle, G., Liu, Y., Tsitsikov, E. N., & Watts, T. H. (2008). ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. Journal of Immunology, 180(12), 8093–8101.

    Article  CAS  Google Scholar 

  • Saoulli, K., Lee, S. Y., Cannons, J. L., Yeh, W. C., Santana, A., Goldstein, M. D., et al. (1998). CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. Journal of Experimental Medicine, 187(11), 1849–1862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schonbeck, U., & Libby, P. (2001). CD40 signaling and plaque instability. Circulation Research, 89(12), 1092–1103.

    Article  CAS  PubMed  Google Scholar 

  • Seo, S. K., Choi, J. H., Kim, Y. H., Kang, W. J., Park, H. Y., Suh, J. H., et al. (2004). 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nature Medicine, 10(10), 1088–1094. doi:10.1038/nm1107.

    Article  CAS  PubMed  Google Scholar 

  • Shao, Z., & Schwarz, H. (2011). CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. Journal of Leukocyte Biology, 89(1), 21–29. doi:10.1189/jlb.0510315.

    Article  CAS  PubMed  Google Scholar 

  • Shuford, W. W., Klussman, K., Tritchler, D. D., Loo, D. T., Chalupny, J., Siadak, A. W., et al. (1997). 4-1BB costimulatory signals preferentially induce CD8+T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. Journal of Experimental Medicine, 186(1), 47–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sica, G., & Chen, L. (2000). Modulation of the immune response through 4-1BB. Advances in Experimental Medicine and Biology, 465, 355–362. doi:10.1007/0-306-46817-4_30.

    Article  CAS  PubMed  Google Scholar 

  • Soderstrom, L. A., Gertow, K., Folkersen, L., Sabater-Lleal, M., Sundman, E., Sheikine, Y., et al. (2014). Human genetic evidence for involvement of CD137 in atherosclerosis. Molecular Medicine, 20, 456–465. doi:10.2119/molmed.2014.00004.

    Article  PubMed  PubMed Central  Google Scholar 

  • Steinberg, H. O., Paradisi, G., Cronin, J., Crowde, K., Hempfling, A., Hook, G., et al. (2000). Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation, 101(17), 2040–2046.

    Article  CAS  PubMed  Google Scholar 

  • Sytwu, H. K., Lin, W. D., Roffler, S. R., Hung, J. T., Sung, H. S., Wang, C. H., et al. (2003). Anti-4-1BB-based immunotherapy for autoimmune diabetes: Lessons from a transgenic non-obese diabetic (NOD) model. Journal of Autoimmunity, 21(3), 247–254.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, C., Mittler, R. S., & Vella, A. T. (1999). Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. Journal of Immunology, 162(9), 5037–5040.

    CAS  Google Scholar 

  • Tournier-Lasserve, E. (2002). New players in the genetics of stroke. New England Journal of Medicine, 347(21), 1711–1712. doi:10.1056/NEJMcibr022035.

    Article  PubMed  Google Scholar 

  • Vinay, D. S., & Kwon, B. S. (1999). Relative abilities of 4-1BB (CD137) and CD28 to co-stimulate the response of cytokine deflected Th1 and Th2 cells. Immunobiology, 200(2), 246–263.

    Article  CAS  PubMed  Google Scholar 

  • Watts, T. H. (2005). TNF/TNFR family members in costimulation of T cell responses. Annual Review of Immunology, 23, 23–68. doi:10.1146/annurev.immunol.23.021704.115839.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, R., Li, X., Liu, N., Guo, X., Liu, W., Ning, C., et al. (2013). An association study on renalase polymorphisms and ischemic stroke in a Chinese population. Neuromolecular Med, 15(2), 396–404. doi:10.1007/s12017-013-8227-0.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, L. F., Yang, J., Hong, Z., Yuan, G. G., Zhou, B. F., Zhao, L. C., et al. (2003). Proportion of different subtypes of stroke in China. Stroke, 34(9), 2091–2096. doi:10.1161/01.str.0000087149.42294.8c.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81671689).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Litao Sun or Jiawei Tian.

Ethics declarations

Conflict of interest

The authors declared no conflict of interest.

Informed Consent

All subjects agreed with the ethics examination and signed informed consent.

Ethical Approval

The research was approved by the ethics committee of 2nd Affiliated Hospital of Harbin Medical University.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, S., Li, Z., Zhang, R. et al. Novel CD137 Gene Polymorphisms and Susceptibility to Ischemic Stroke in the Northern Chinese Han Population. Neuromol Med 19, 413–422 (2017). https://doi.org/10.1007/s12017-017-8457-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-017-8457-7

Keywords

Navigation