Toll-like receptor 4 polymorphisms and atherogenesis - PubMed (original) (raw)
Comparative Study
. 2002 Jul 18;347(3):185-92.
doi: 10.1056/NEJMoa012673.
Affiliations
- PMID: 12124407
- DOI: 10.1056/NEJMoa012673
Free article
Comparative Study
Toll-like receptor 4 polymorphisms and atherogenesis
Stefan Kiechl et al. N Engl J Med. 2002.
Free article
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.
Copyright 2002 Massachusetts Medical Society.
Comment in
- Toll-like receptor 4 polymorphisms and atherogenesis.
Cooke GS, Segal S, Hill AV; Tuberculosis, Genetics, and Environment (TBGENENV) Study Group; Oxford Pneumococcal Surveillance Study Group. Cooke GS, et al. N Engl J Med. 2002 Dec 12;347(24):1978-80; author reply 1978-80. doi: 10.1056/NEJM200212123472416. N Engl J Med. 2002. PMID: 12477953 No abstract available. - Toll-like receptor 4 polymorphisms and atherogenesis.
Beutler B, Beutler E. Beutler B, et al. N Engl J Med. 2002 Dec 12;347(24):1978-80; author reply 1978-80. N Engl J Med. 2002. PMID: 12479194 No abstract available.
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