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ABSTRACT

Background The ability to mount a prominent inflammatory response to bacterial pathogens confers an advantage in innate immune defense but may signal an increased risk of atherosclerosis. We determined whether recently discovered genetic variants of toll-like receptor 4 (TLR4) that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide are related to 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 TLR4 polymorphisms Asp299Gly and Thr399Ile. The extent and progression of carotid atherosclerosis were assessed by high-resolution duplex ultrasonography.

Results As compared with subjects with wild-type TLR4, the 55 subjects with the Asp299Gly TLR4 allele had lower levels of certain proinflammatory cytokines, acute-phase reactants, and soluble adhesion molecules, such as interleukin-6 and fibrinogen. Although these subjects were found to be more susceptible to severe bacterial infections, they had a lower risk of carotid atherosclerosis (odds ratio, 0.54; 95 percent confidence interval, 0.32 to 0.98; P=0.05) and a smaller intima–media thickness in 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 attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens, is associated with a decreased risk of atherosclerosis. This finding is consistent with the hypothesis that 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.

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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. Correspondence

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