The presence of the Asp299Gly allele of the TLR4 gene does not seem to exert a major influence on the progression of atherosclerosis in patients with FH.
In summary, results in our study do not support the hypothesis that the rs4986790 (+896A>G, rs4986790" genes_norm="7099">Asp299Gly) TLR4 variant may influence predisposition for subclinical atherosclerosis and clinically evident CV disease in RA patients.
Moreover, further subgroup analyses revealed that TLR4rs1927911 polymorphism was significantly associated with the risk of cerebral infarction in the recessive model (95% CI 0.46-0.96), whereas TLR4rs4986791 polymorphism was significantly correlated with susceptibility to atherosclerosis among Asians in the dominant (95% CI 1.58-6.66), additive (95% CI 0.13-0.69) and allele (95% CI 1.58-5.53) models.
Atherosclerosis resulting in cerebral or carotid arterial stenosis/occlusion plays the most important role in the occurrence of cerebral infarction (CI), and thus TLR4 polymorphisms may influence formation of atherosclerosis and the development of CI.
We furthermore compared the frequency of both SNPs in the patients with an age-matched group of individuals without atherosclerosis and found a trend towards a lower frequency of the TLR-4 SNP in the atherosclerotic group (PTCA: 5.58; PTCA/stent: 3.85 versus 7.14%).
Trend analysis showed that the TLR4 +866 G allele frequency increased with the number of vascular territories affected by clinically relevant atherosclerosis (P trend, .0074).
The Asp299GlyTLR4 polymorphism, which attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens, is associated with a decreased risk of atherosclerosis.
One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied.
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.
Polymorphisms in Toll-like receptor-4 (TLR4) have been reported to be associated with a blunted immune response to microbial pathogens, as well as a decreased risk of atherosclerosis in the general population.
The G allele of the Toll-like receptor 4 (TLR-4) gene Asp299Gly polymorphism has been previously associated with decreased development of atherosclerosis and with lower risk of myocardial infractions.
Examples include variants of TLR4 in sepsis, malaria, inflammatory bowel disease and atherosclerosis; variants in TLR2 in tuberculosis and asthma; a variant in Mal (a key signal for TLR2 and TLR4) in malaria, tuberculosis and systemic lupus erythematosus; and variants in the kinase IRAK4 in pyogenic infections.
1400 participants (mean age: 63 years, 31% female) in the Southampton Atherosclerosis Study were genotyped for the TLR4Asp299Gly polymorphism using the tetra-primer PCR method.
Genetic ablation of TLR4 partially reversed atherosclerosis exacerbation in EDA(fl/fl)Apoe(-/-) mice (P<0.05) but had no effect on atherosclerotic lesions in EDA(-/-)Apoe(-/-) mice.
Moreover, our data offer an explanation for the comparable effects of IFNα or IFNγ priming on TLR4-induced activation in vascular and immune cells, with important implications in atherosclerosis.