Receptor Variant that Confers Decreased Immune Function is a Marker for Resistance to Atherosclerosis

David A. Schwartz
Duke University Medical Center
R01ES07498, P01ES09607, and U19ES11375

Background: The ability to mount a prominent inflammatory response to a bacterial challenge confers an advantage in innate immune defense; however, the effects of intravascular inflammation lead to proatherogenic effects. The focus of this study was to determine if genetic variants in the toll-like receptor 4 (TLR4) that confer differences in the inflammatory response due to bacterial lipopolysaccharide are related to the development of atherosclerosis. The hypothesis tested was that efficient immune defense offers an early advantage but at a cost of chronic vascular damage in later years.

Advance: An epidemiologic study was carried out in 810 persons in which the team screened for TLR4 polymorphisms. The extent and progression of atherosclerosis was also assessed. Fifty-five individuals were found to have the Asp299Gly TLR4 polymorphism. These individuals had lower levels of certain proinflammatory cytokines and other inflammatory agents. While these subjects were more susceptible to severe bacterial infections, they had an almost 50% reduction in the risk of carotid arterial atherosclerosis.

Implications: The polymorphism identified in this study attenuates receptor signaling and diminishes the inflammatory response to gram negative bacteria along with decreasing the risk of atherosclerosis. This study provides further evidence that an efficient innate immune defense against bacteria is associated with long-term intravascular inflammatory stress leading to the development of atherosclerosis.

Citation: Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonara E, Williet J, Schwartz DA. Toll-like receptor 4 polymorphisms and atherogenesis. New England Journal of Medicine 2002, 347; 3:185-192.