Association of a common TLR-6 polymorphism with coronary artery disease – implications for healthy ageing?

Abstract

BackgroundThe pro-inflammatory status of the elderly triggers most of the age-related diseases such as cancer and atherosclerosis. Atherosclerosis, the leading cause world wide of morbidity and death, is an inflammatory disease influenced by life-style and genetic host factors. Stimuli such as oxLDL or microbial ligands have been proposed to trigger inflammation leading to atherosclerosis. It has recently been shown that oxLDL activates immune cells via the Toll-like receptor (TLR) 4/6 complex. Several common single nucleotide polymorphisms (SNPs) of the TLR system have been associated with atherosclerosis. To investigate the role of TLR-6 we analyzed the association of the TLR-6 SNP Pro249Ser with atherogenesis.ResultsGenotyping of two independent groups with CAD, as well as of healthy controls revealed a significant association of the homozygous genotype with a reduced risk for atherosclerosis (odds ratio: 0.69, 95% CI 0.51-0.95, P = 0.02). In addition, we found a trend towards an association with the risk of restenosis after transluminal coronary angioplasty (odds ratio: 0.53, 95% CI 0.24-1.16, P = 0.12). In addition, first evidence is presented that the frequency of this protective genotype increases in a healthy population with age. Taken together, our results define a role for TLR-6 and its genetic variations in modulating the inflammatory response leading to atherosclerosis.ConclusionsThese results may lead to a better risk stratification, and potentially to an improved prophylactic treatment of high-risk populations. Furthermore, the protective effect of this polymorphism may lead to an increase of this genotype in the healthy elderly and may therefore be a novel genetic marker for the well-being during aging.

Relationship between toll-like receptor 2 Arg677Trp and Arg753Gln and toll-like receptor 4 Asp299Gly polymorphisms and cytomegalovirus infection

“…It was found that homozygosity for the TLR6 Pro249Ser genotype protects from atherosclerosis, and a significant increase in the frequency of the Pro249Ser SNP with age was observed. 22 Hamann et al speculate that this TLR6 variant may confer its beneficial effects by decreasing inflamm-ageing during older age. 22 Little is known about the role of TLR SNPs in the pathogenesis of CMV infection in humans.…”

“…22 Hamann et al speculate that this TLR6 variant may confer its beneficial effects by decreasing inflamm-ageing during older age. 22 Little is known about the role of TLR SNPs in the pathogenesis of CMV infection in humans. The clinical relevance of TLR2 and TLR4 polymorphism has previously been suggested only in immunocompromised populations.…”

“…Diminished signalling in cells that express polymorphic TLRs, particularly when both mutations are expressed on the same protein, may decrease the ability to control infection and thereby increase susceptibility to multiple pathogens. 2,22 It has previously been found that the Arg677Trp substitution in the intracellular MyD88-binding domain and the Arg753Gln polymorphism in the C-terminal of TLR2 may impair the host response to microbial pathogens. [34][35][36] We suppose that the T allele of Arg677Trp may affect the transcription, synthesis, and transport of TLR2 and therefore also affect the function of TLR2 protein.…”

Microbial modulation of cardiovascular disease

“…The heterodimeric complex of toll like receptors (TLR) 2 and TLR6 (TLR2-TLR6) is central to sensing bacterial di- and tri-acylated peptides 35,36 . A recently described SNP in the Tlr6 gene has been linked to left ventricular wall thickening and markers of inflammation 37,38 , and Tlr2 −/− mice have strikingly reduced atherosclerosis, especially when challenged with synthetic TLR2 agonists 36 . Furthermore, transplantation of bone marrow from mice lacking the double-strand DNA receptor TLR3 into LDLr −/− , which is a commonly used mouse model of atherosclerosis driven by elevated low density lipoprotein cholesterol levels mice results in reduced atherosclerosis burden 39 .…”

Genomic Factors (Toll-Like Receptors Genes) in Development of Atherosclerosis and Its Clinical Manifestations

“…Сам ген TLR6 локализован на коротком плече четвертой хромосомы (4р13). При наличии вариантного аллеля по rs5743810 гена TLR6 (замена серина [Ser] пролином [Pro] в позиции 249), что приводит к снижению воспалительного ответа [25,57].…”