Abstract
Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis. Two biallelic polymorphisms in the TNF-α (TNF-α-308) and TNF-β (TNF-β +252) genes have been reported to be associated with TNF production and susceptibility to inflammatory diseases. We investigated two genetic polymorphisms in the TNF locus (TNF-α-308 G→A and TNF-β +252 A→G) as risk factors for cerebral infarction (CI) by determining its prevalence in 294 survivors of CI, and in 581 age-, gender-, and race-matched controls. A significant association was found for the TNF-α and TNF-β genotypes in CI patients compared with controls. A significant increase was found for the TNF-α A allele in controls compared with CI patients (X 2=7.593, p=0.006, odds ratio =1.74, confidence interval =1.17-2.59). In addition, the TNF-α GG genotype increased the relative risk for CI in subjects with the TNF-β AA genotype (X 2 = 4.998, P=0.025). As a result, compared to controls, the frequency of the TNF-α AA genotype was decreased, whereas that of TNF-β AA was increased in CI patients. The former implies an association with resistance, whereas the latter suggests an association with susceptibility to the disease. These results show that the TNF-α-308 and TNF-β + 252 locus plays an important role in the etiopathogenesis of CI.
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Andreotti F., Portol I., Crea F., and Maseri A. (2000) Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies. Heart 87, 107–112.
Barath P., Fishbein M. C., Cao J., Berensen J., Helfant R. H., and Forrester J. S. (1990) Detection and localization of tumor necrosis factor in human atheroma. Am. J. Cardiol. 65, 297–302.
Bazzoni F. and Beutler B. (1996) The tumor necrosis factor ligand and receptor families. N. Engl. J. Med. 334, 1717–1725.
Braun N., Michel U., Ernst B. P., Metzner R, Bitsch A., Weber F., et al. (1996) Gene polymorphism at position -308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and its influence on the regulation of TNF-alpha production. Neurosci. Lett. 215, 75–78.
Cabrera M., Shaw M. A., Sharples C., Williams H., Castes M., Convit J., et al. (1995) Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J. Exp. Med. 182, 1259–1264.
Cheng B., Christakos S., and Mattson M. P. (1994) Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153.
Collier P. M., Wojnarowska F., McGuire B., and Welsh K. I. (1994) Polymorphism of tumor necrosis factor α promoter region of the MHC is strongly associated with linear IgA disease and affects prognosis. Br. J. Dermatol. 131, 22.
DeGraba T. J. (1997) Expression of inflammatory mediators and adhesion molecules in human atherosclerotic plaque. Neurology 49, S515-S519.
Maseri A. (1997) Inflammation, atherosclerosis, and ischemic events—exploring the hidden side of the moon. N. Engl. J. Med. 336, 1014–1016.
McGuire W., Hill A. V., Allsopp C. E. M., Greenwood B. M., and Kwiatkowski D. (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371, 508–510.
Messer G., Spengler U., Jung M. C., Honold G., Blomer K., Pape G. R., et al. (1991) Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. J. Exp. Med. 173, 209–219.
Miller S. A., Dykes D. D., and Polesky H. F. (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215.
Pociot F., Briant L., Jongeneel C. V., Molvig J., Worsaae H., Abbal M., et al. (1993) Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur. J. Immunol. 23, 224–231.
Ross R. (1999) Atherosclerosis—an inflammatory disease. New Engl. J. Med. 340, 115–126.
Selwyn A. P., Kinlay S., and Ganz P. (1997) Atherogenesis and ischemic heart disease. Am. J. Cardiol. 80, 3H-7H.
Stuber F., Petersen M., Bokelmann F., and Schade U. (1996) A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit. Care Med. 24, 381–384.
Um J. Y., Kim H. J., Choi T. J., Jin C. S., Park S. T., Lee K. C., et al. (2001) Polymorphism of the angiotensin-converting enzyme gene in patients with cerebral infarction in Koreans. J. Mol. Neurosci. 17, 279–283.
Um J. Y., An N. H., Kim S. H., Lee K. M., Kim Y. S., Jang H., et al. (2003a) Genetic susceptibility to ischemic cerebrovascular disease in Koreans. J. Mol. Neurosci. 20, 31–38.
Um J. Y., Moon K. S., Lee K. M., Cho K. H., Heo Y., Moon B. S., et al. (2003b) Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in patients with cerebral infarction in Koreans. J. Mol. Neurosci. 21, 23–28.
Warzocha K., Ribeiro P., Bienvenu J., Roy P., Charlot C., Rigal D., et al. (1998) Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome. Blood 91, 3574–3581.
Wilson A. G., Clay F. E., Crane A. M., Cork M. J., and Duff G. W. (1995) Genetics of tumor necrosis factor alpha in dermatitis herpetiformis. J. Invest. Dermatol. 104, 856–858.
Wilson A. G., DiGiovine F. S., and Duff G. W. (1995) Genetics of tumor necrosis factor-alpha in autoimmune, infectious, and neoplastic diseases. J. Inflamm. 45, 1–12.
Wilson A. G., Symons J. A., McDowell T. L., McDevitt H. O., and Duff G. W. (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc. Natl. Acad. Sci. USA 94, 3195–3199.
Woods A., Brull D. J., Humphries S. E., and Montgomery H. E. (2000) Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6. Eur. Heart J. 21, 1574–1583.
Wu W. S. and McClain K. L. (1997) DNA polymorphisms and mutation of the tumor necrosis-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH). J. Interferon Cytokine Res. 17, 631–635.
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Um, JY., An, NH. & Kim, HM. TNF-α and TNF-β gene polymorphisms in cerebral infarction. J Mol Neurosci 21, 167–171 (2003). https://doi.org/10.1385/JMN:21:2:167
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DOI: https://doi.org/10.1385/JMN:21:2:167