Toll-like receptor 4 polymorphisms and atherogenesis

N Engl J Med. 2002 Jul 18;347(3):185-92. doi: 10.1056/NEJMoa012673.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Arteriosclerosis / diagnostic imaging
  • Arteriosclerosis / genetics*
  • Bacterial Infections / genetics
  • Carotid Arteries / diagnostic imaging
  • Carotid Artery Diseases / diagnostic imaging
  • Carotid Artery Diseases / genetics
  • Drosophila Proteins*
  • Female
  • Follow-Up Studies
  • Humans
  • Inflammation / genetics
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / physiology
  • Middle Aged
  • Multivariate Analysis
  • Polymorphism, Genetic
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Ultrasonography


  • Drosophila Proteins
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors