Toll-like receptor 4 polymorphisms and atherogenesis.
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.
Department of Neurology, University Clinic, Innsbruck, Austria. stefan.kiechl@uibk.ac.at
Stefan
S
Kiechl
Eva
E
Lorenz
Markus
M
Reindl
Christian J
CJ
Wiedermann
Friedrich
F
Oberhollenzer
Enzo
E
Bonora
Johann
J
Willeit
David A
DA
Schwartz
D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000000981:diagnostic imaging / Q000235:genetics*; D001424:Bacterial Infections / Q000235:genetics; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000235:genetics; D029721:Drosophila Proteins; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014463:Ultrasonography
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors