Toll-like Receptor 4 Polymorphisms and Atherogenesis
Stefan Kiechl, M.D., Eva Lorenz, Ph.D., Markus Reindl, Ph.D., Christian J. Wiedermann, M.D., Friedrich Oberhollenzer, M.D., Enzo Bonora, M.D., Johann Willeit, M.D., and David A. Schwartz, M.D.
Background The ability to mount a prominent inflammatory responseto bacterial pathogens confers an advantage in innate immunedefense but may signal an increased risk of atherosclerosis.We determined whether recently discovered genetic variants oftoll-like receptor 4 (TLR4) that confer differences in the inflammatoryresponse elicited by bacterial lipopolysaccharide are relatedto the development of atherosclerosis.
Methods As part of the five-year follow-up in the Bruneck (Italy)Study, we screened 810 persons in the study cohort for the TLR4polymorphisms Asp299Gly and Thr399Ile. The extent and progressionof carotid atherosclerosis were assessed by high-resolutionduplex ultrasonography.
Results As compared with subjects with wild-type TLR4, the 55subjects with the Asp299Gly TLR4 allele had lower levels ofcertain proinflammatory cytokines, acute-phase reactants, andsoluble adhesion molecules, such as interleukin-6 and fibrinogen.Although these subjects were found to be more susceptible tosevere bacterial infections, they had a lower risk of carotidatherosclerosis (odds ratio, 0.54; 95 percent confidence interval,0.32 to 0.98; P=0.05) and a smaller intima–media thicknessin the common carotid artery (regression coefficient, –0.07;95 percent confidence interval, –0.12 to –0.02;P=0.01).
Conclusions The Asp299Gly TLR4 polymorphism, which attenuatesreceptor signaling and diminishes the inflammatory responseto gram-negative pathogens, is associated with a decreased riskof atherosclerosis. This finding is consistent with the hypothesisthat innate immunity may play a part in atherogenesis.
Source Information
From the Departments of Neurology (S.K., M.R., J.W.) and Internal Medicine (C.J.W.), University Clinic, Innsbruck, Austria; Wake Forest University Medical School, Winston-Salem, N.C. (E.L.); the Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy (F.O.); the Department of Endocrinology and Metabolism, University of Verona, Verona, Italy (E.B.); and the Department of Medicine and Genetics, Duke University Medical Center and Veterans Affairs Medical Center, Durham, N.C. (D.A.S.).
Address reprint requests to Dr. Kiechl at the Department of Neurology, Innsbruck University Clinic, Anichstr. 35, A-6020 Innsbruck, Austria, or at stefan.kiechl{at}uibk.ac.at.
Toll-like Receptor 4 Polymorphisms and Atherogenesis
Cooke G. S., Segal S., Hill A. V.S., the Tuberculosis, Genetics, and Environment (TBGENENV) and the Oxford Pneumococcal Surveillance Study Groups , Beutler B., Beutler E., Kiechl S., Willeit J., Schwartz D. A.
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N Engl J Med 2002;
347:1978-1980, Dec 12, 2002.
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Methe, H., Kim, J.-O., Kofler, S., Weis, M., Nabauer, M., Koglin, J.
(2005). Expansion of Circulating Toll-Like Receptor 4-Positive Monocytes in Patients With Acute Coronary Syndrome. Circulation
111: 2654-2661
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Singh, B. N.
(2005). Atrial Fibrillation: The Rate or Rhythm Controversy Can It be Resolved on the Basis of Clinical Trial Data?. J CARDIOVASC PHARMACOL THER
10: 81-83
Palmer, S. M., Burch, L. H., Trindade, A. J., Davis, R. D., Herczyk, W. F., Reinsmoen, N. L., Schwartz, D. A.
(2005). Innate Immunity Influences Long-term Outcomes after Human Lung Transplant. Am. J. Respir. Crit. Care Med.
171: 780-785
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Schoneveld, A.H., Oude Nijhuis, M.M., van Middelaar, B., Laman, J.D., de Kleijn, D.P.V., Pasterkamp, G.
(2005). Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res
66: 162-169
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Rittersma, S. Z.H., Kremer Hovinga, J. A., Koch, K. T., Boekholdt, S. M., van Aken, B. E., Scheepmaker, A., Bax, M., Schotborgh, C. E., Piek, J. J., Tijssen, J. G.P., Reitsma, P. H., de Winter, R. J.
(2005). Relationship between In Vitro Lipopolysaccharide-Induced Cytokine Response in Whole Blood, Angiographic In-Stent Restenosis, and Toll-Like Receptor 4 Gene Polymorphisms. Clin. Chem.
51: 516-521
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Hawn, T. R., Verbon, A., Janer, M., Zhao, L. P., Beutler, B., Aderem, A.
(2005). Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease. Proc. Natl. Acad. Sci. USA
102: 2487-2489
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Furtner, M., Kiechl, S., Mair, A., Seppi, K., Weger, S., Oberhollenzer, F., Poewe, W., Willeit, J.
(2005). Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population. Eur Heart J
26: 279-287
[Abstract][Full Text]
Leth-Larsen, R., Garred, P., Jensenius, H., Meschi, J., Hartshorn, K., Madsen, J., Tornoe, I., Madsen, H. O., Sorensen, G., Crouch, E., Holmskov, U.
(2005). A Common Polymorphism in the SFTPD Gene Influences Assembly, Function, and Concentration of Surfactant Protein D. J. Immunol.
174: 1532-1538
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Goodridge, H. S., Marshall, F. A., Else, K. J., Houston, K. M., Egan, C., Al-Riyami, L., Liew, F.-Y., Harnett, W., Harnett, M. M.
(2005). Immunomodulation via Novel Use of TLR4 by the Filarial Nematode Phosphorylcholine-Containing Secreted Product, ES-62. J. Immunol.
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Zee, R. Y.L., Hegener, H. H., Gould, J., Ridker, P. M.
(2005). Toll-like Receptor 4 Asp299Gly Gene Polymorphism and Risk of Atherothrombosis. Stroke
36: 154-157
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VanderMeer, J., Sha, Q., Lane, A. P., Schleimer, R. P.
(2004). Innate Immunity of the Sinonasal Cavity: Expression of Messenger RNA for Complement Cascade Components and Toll-like Receptors. Arch Otolaryngol Head Neck Surg
130: 1374-1380
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Stoll, L. L., Denning, G. M., Weintraub, N. L.
(2004). Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
24: 2227-2236
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Berg, A. H., Lin, Y., Lisanti, M. P., Scherer, P. E.
(2004). Adipocyte differentiation induces dynamic changes in NF-{kappa}B expression and activity. Am. J. Physiol. Endocrinol. Metab.
287: E1178-E1188
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Bornstein, S. R., Zacharowski, P., Schumann, R. R., Barthel, A., Tran, N., Papewalis, C., Rettori, V., McCann, S. M., Schulze-Osthoff, K., Scherbaum, W. A., Tarnow, J., Zacharowski, K.
(2004). Impaired adrenal stress response in Toll-like receptor 2-deficient mice. Proc. Natl. Acad. Sci. USA
101: 16695-16700
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Balistreri, C. R., Candore, G., Colonna-Romano, G., Lio, D., Caruso, M., Hoffmann, E., Franceschi, C., Caruso, C.
(2004). Role of Toll-like Receptor 4 in Acute Myocardial Infarction and Longevity. JAMA
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Michelsen, K. S., Doherty, T. M., Shah, P. K., Arditi, M.
(2004). TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis. J. Immunol.
173: 5901-5907
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Singh, B. N.
(2004). Pursuit of Sinus Rhythm in Patients with Atrial Fibrillation: Is the Effort Worth It?. J CARDIOVASC PHARMACOL THER
9: 219-221
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