title: Effects of toll-like receptor-4 gene polymorphisms on soluble P-selectin and von Willebrand factor levels in hypercholesterolemic patients.
abstract: Toll-like receptor-4 (TLR-4) gene polymorphisms have been associated with a lower risk of atherosclerosis. High levels of soluble P-selectin (sP-selectin) and von Willebrand factor predict an increased risk for cardiovascular events and correlate to atherosclerotic risk factors. The relationship between these markers and TLR-4 gene polymorphisms was evaluated in a cohort of consecutive hypercholesterolemic outpatients. TLR-4 gene polymorphisms were detected in 48 out of 330 (14%) patients with hypercholesterolemia. Lipid and inflammatory markers, sP-selectin and von Willebrand were evaluated in carriers and in 96 (ratio 2:1 to cases) age- and sex-matched TLR-4 wild-type patients randomly selected from the same population. A cohort of normocholesterolemic outpatients (n = 262) served as the control group. sP-selectin was sensibly lower in carriers of TLR-4 variants as compared to wild-types and controls (89 ng/ml vs. 162 ng/ml and 163 ng/dl, respectively, p = 0.0001). Similarly, carriers showed lower von Willebrand factor values (683 mU/ml) than wild-types (910 mU/ml; p = 0.001). In multivariate analysis, TLR-4 gene polymorphisms were positively associated with sP-selectin, whereas the relationship with von Willebrand factor was no longer significant. HMG-CoA reductase inhibitors reduced sP-selectin and von Willebrand factor levels independently of TLR-4 gene variants. Plasma concentrations of these markers, however, remained lower in carriers of TLR-4 gene polymorphisms even after cholesterol lowering. In conclusion, carriership of Asp299 and Thr399Ile TLR-4 gene polymorphisms is associated with lower levels of sP-selectin and von Willebrand factor among hypercholesterolemic patients. While the underlying mechanisms remain to be investigated, such an association may indicate a protective effect of TLR-4 variants for atherosclerosis.
authors.affiliation: Department of Medicine and Aging, Aging Research Center, Ce.S.I., G. D'Annunzio University Foundation, Chieti-Pescara, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Di Nisio
authors.forename: Concetta
authors.initials: C
authors.lastname: Di Febbo
authors.forename: Valeria
authors.initials: V
authors.lastname: Moretta
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Guglielmi
authors.forename: Liborio
authors.initials: L
authors.lastname: Stuppia
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: Ettore
authors.initials: E
authors.lastname: Porreca
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000517:prevention & control; D000069059:Atorvastatin; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000627:therapeutic use*; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D016896:Treatment Outcome; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D019007:P-Selectin; D011758:Pyrroles; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014841:von Willebrand Factor; D000069059:Atorvastatin