Abstract
A direct role of lymphotoxin-α (LTA) in promoting atherosclerotic plaque growth has been demonstrated recently. The different protein transcripts of the naturally occurring genetic variants of the LTA gene have been demonstrated to exhibit affected functions, and an allelic difference in binding to transcription factor(s) has also been suggested. The homozygous variant of LTA characterized by the intron 1 252A→G (252G) transition, which naturally coexists with an exon 3 804C→A (804A) single-nucleotide polymorphism (SNP), has been reported as a susceptibility gene for myocardial infarction. Because the atherosclerotic process is also an integral component in the pathogenesis of certain types of vascular stroke, we investigated the possible significance of the above SNPs in 353 ischemic stroke patients and 180 healthy controls. The homozygous LTA allele with the 252G and 804C SNPs occurred more frequently in stroke patients (13.9%) than in controls (7.20%, p<0.025). Specific subclassification of the patients revealed an accumulation of these SNPs in large-vessel, pathology-associated cerebral infarction (18.2%); multivariate logistic regression analysis of the data confirmed this association, with an odds ratio of 2.1 (95% confidence interval, 1.3–6.2; p<0.005). Elimination of all subjects with a history or evidence of ischemic heart disease, including myocardial infarction, did not affect this association. These data show that besides the role in the development of myocardial infarction, the homozygous carriage of the LTA allele with 252G and 804A SNPs is a novel susceptibility factor for largevesselassociated ischemic stroke.
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Belch J. J., Shaw J. W., Kirk G., McLaren M., Robb R., Maple C., and Morse P. (1997) The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermittent claudication undergoing percutaneous transluminal angioplasty. Circulation 95, 2027–2031.
Fisher C. M. (1998) Lacunes: small, deep cerebral infarcts. Neurology 50, 841.
Hassan A. and Markus H. S. (2000) Genetics and ischaemic stroke. Brain 123, 1784–1812.
Hwang S. J., Ballantyne C. M., Sharrett A. R., Smith L. C., Davis C. E., Gotto A. M. Jr., and Boerwinkle E. (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96, 4219–4225.
Kobayashi S., Okada K., and Yamashita K. (1991) Incidence of silent lacunar lesion in normal adults and its relation to cerebral blood flow and risk factors. Stroke 22, 1379–1383.
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 Ncol 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, 1215–1218.
Morisaki N., Saito I., Tamura K., Tashiro J., Masuda M., Kanzaki T., et al. (1997) New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease. Atherosclerosis 131, 43–48.
O’Brien K. D., McDonald T. O., Chait A., Allen M. D., and Alpers C. E. (1996) Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 93, 672–682.
Ozaki K., Ohnishi Y., Iida A., Sekine A., Yamada R., Tsunoda T., et al. (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654.
Pessin M. S., Hinton R. C., Davis K. R., Duncan G. W., Roberson G.H., Ackerman R.H., and Mohr J.P. (1979) Mechanisms of acute carotid stroke. Ann. Neurol. 6, 245–252.
Price T. R., Manolio T. A., Kronmal R. A., Kittner S. J., Yue N. C., Robbins J., et al. (1997) Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Stroke 28, 1158–1164.
Ross R. (1999) Atherosclerosis is an inflammatory disease. Am. Heart. J. 138, S419-S420.
Schreyer S. A., Vick C. M., and LeBoeuf R. C. (2002) Loss of lymphotoxin-alpha but not tumor necrosis factor-alpha reduces atherosclerosis in mice. J. Biol. Chem. 277, 12364–12368.
Schulz U. G. and Rothwell P. M. (2003) Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 34, 2050–2059.
Shinkawa A., Ueda K., Kiyohara Y., Kato I., Sueishi K., Tsuneyoshi M., and Fujishima M. (1995) Silent cerebral infarction in a community-based autopsy series in Japan. The Hisayama Study. Stroke 26, 380–385.
Squadrito F., Saitta A., Altavilla D., Ioculano M., Canale P., Campo G. M., et al. (1996) Thrombolytic therapy with urokinase reduces increased circulating endothelial adhesion molecules in acute myocardial infarction. Inflamm. Res. 45, 14–19.
Szolnoki Z., Somogyvari F., Kondacs A., Szabo M., Bene J., Havasi V., et al. (2003a) Increased prevalence of platelet glycoprotein IIb/IIIa PLA2 allele in ischaemic stroke associated with large vessel pathology. Thromb. Res. 109, 265–269.
Szolnoki Z., Somogyvari F., Kondacs A., Szabo M., and Fodor L. (2002) Evaluation of the interactions of common genetic mutations in stroke subtypes. J. Neurol. 249, 1391–1397.
Szolnoki Z., Somogyvari F., Kondacs A., Szabo M., Fodor L., Bene J., and Melegh B. (2003b) Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke. J. Neurol. Neurosurg. Psychiatry 74, 1615–1620.
Um J. Y., An N. H., Kim S. H., Lee K. M., Kim Y. S., Jang H., et al. (2003) Genetic susceptibility to ischemic cerebrovascular disease in Koreans. J. Mol. Neurosci. 20, 31–38.
Ware C. F., VanArsdale T. L., Crowe P. D., and Browning J. L. (1995) The ligands and receptors of the lymphotoxin system. Curr. Top. Microbiol. Immunol. 198, 175–218.
World Health Organization (1985) Report on diabetes mellitus. WHO Tech. Rep. Ser. 727.
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Szolnoki, Z., Havasi, V., Talián, G. et al. Lymphotoxin-α gene 252G allelic variant is a risk factor for large-vessel-associated ischemic stroke. J Mol Neurosci 27, 205–211 (2005). https://doi.org/10.1385/JMN:27:2:205
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DOI: https://doi.org/10.1385/JMN:27:2:205