Toll-like Receptor Polymorphisms and Carotid Artery Intima-Media Thickness
To the Editor:
Chronic inflammation represents a hallmark of atherosclerosis. Thus, there is growing interest in the role of innate immune defense mechanisms in arterial plaque formation, and several studies directly implicate signaling by toll-like receptors (TLRs) in the pathogenesis of atherosclerosis. However, these links are not completely understood, and further studies determining the clinical relevance of TLRs in atherosclerosis are clearly needed.
We thus read with interest the article of Labrum et al.1 In a large prospective setting they studied 2 single nucleotide polymorphisms in TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly) and their association with the progression of intima-media thickness. The study did not confirm previous smaller studies demonstrating that there are significant associations between genetic variation in these two TLRs and increased intima-media thickness.
Because TLRs have been recognized as pivotal receptors for innate immune recognition, there have been several studies in which healthy as well as defined patient populations were screened for polymorphisms in tlr2 or tlr4 genes. To date, results have been inconclusive.1,2 Although we subscribe to the view of Labrum et al that these polymorphisms may not be associated with development and course of atherosclerosis, we prefer a more functional explanation that may also clarify to some extent the heterogeneous results obtained so far.
It has been reported that two cosegregating variants of TLR4 attenuate LPS signaling and are accompanied by LPS hyporesponsiveness.5 However, further studies revealed other genes and receptors to be clearly involved in modulating the response to lipopolysaccharides.6,7 Moreover, recent studies reported that heterozygous polymorphisms of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly) do not suffice to alter the response of monocytes exposed to lipoteichoic acid and lipopolysaccharides, respectively.2–4 In the study of von Aulock et al,2 even an individual who was homozygous for a TLR-4 polymorphism showed no difference in responses to lipopolysaccharides as compared with wild-type individuals. Finally, it has been claimed that these TLR polymorphisms represent functional knockouts of lipoteichoic acid and lipopolysaccharide signaling. Hence, growing evidence suggests that alternative LPS-recognizing molecules may compensate TLR signaling in the case of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly).7 Apart from the functional relevance, the overall low incidence of individuals with homozygous polymorphisms (<1%) makes these polymorphisms a risk factor of lesser demographic importance.2
In summary, recent research has clearly demonstrated the important role of innate immunity in the development of atherosclerosis. However, with respect to the aforementioned arguments, we believe that comparing TLR-2 and TLR-4 polymorphisms with a macroscopic surrogate marker like intima-media thickness may be beyond the possibilities of these single features. Further studies are needed to define the role of intact TLR signaling in the initiation and progression of atherosclerosis.
Labrum R, Bevan S, Sitzer M, Lorenz M, Markus HS: Toll Receptor Polymorphisms and Carotid Artery Intima-Media Thickness. Stroke. 2007; 38: 1179–1184.
von Aulock S, Schroder NW, Gueinzius K, Traub S, Hoffmann S, Graf K, Dimmeler S, Hartung T, Schumann RR, Hermann C. Heterozygous toll-like receptor 4 polymorphism does not influence lipopolysaccharide-induced cytokine release in human whole blood. J Infect Dis. 2003; 188: 938–943.
von Aulock S, Schroder NW, Traub S, Gueinzius K, Lorenz E, Hartung T, Schumann RR, Hermann C. Heterozygous toll-like receptor 2 polymorphism does not affect lipoteichoic acid-induced chemokine and inflammatory responses. Infect Immun. 2004; 72: 1828–1831.
Erridge C, Stewart J, Poxton IR. Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the Toll-like receptor 4 gene show no deficit in lipopolysaccharide signalling. J Exp Med. 2003; 197: 1787–1791.
Lorenz E, Jones M, Wohlford-Lenane C, Meyer N, Frees KL, Arbour NC, Schwartz DA. Genes other than TLR4 are involved in the response to inhaled LPS. Am J Physiol Lung Cell Mol Physiol. 2001; 281: L1106–L1114.