title: A functional nonsynonymous toll-like receptor 4 gene polymorphism is associated with metabolic syndrome, surrogates of insulin resistance, and syndromes of lipid accumulation.
abstract: Toll-like receptor 4 (TLR4) plays a key role in the activation of innate immune responses. Loss-of-function mutations in TLR4 prevent diet-induced obesity and insulin resistance (IR). We conducted a population cross-sectional study to evaluate whether Asp299Gly (rs4986790) TLR4 gene polymorphism is associated with metabolic syndrome (MS), surrogates of IR, and syndromes of lipid accumulation (SLAs) in Argentinean healthy male subjects. rs4986790 was genotyped in 621 healthy unrelated male blood donors. National Cholesterol Education Program/Adult Treatment Panel III-MS (NCEP/ATP III-MS); SLAs such as enlarged waist elevated triglyceride syndrome (EWET), hypertriglyceridemic waist (HW), and overweight-lipid syndrome (OLS); and surrogates of IR were assessed. The prevalence of MS, OLS, and EWET was significantly higher among Asp299Asp carriers (P < .05). These findings were confirmed using 32 000 bootstrap samples. Surrogate markers of IR were also significantly higher in Asp299Asp carriers (P < .05). Most findings were especially strengthened among individuals with C-reactive protein below the 95th percentile and/or total cholesterol to high-density lipoprotein cholesterol ratio >or=5. This is the first report to find, in Argentinean healthy male blood donors, associations between the Asp299Asp genotype of rs4986790 TLR4 gene polymorphism and high risk for NCEP/ATP III-MS, SLAs, and surrogates of IR. These findings are consistent with previous functional and observational studies showing that Asp299 allele, in comparison with Gly299, is associated with increased TLR4 activation, higher levels of inflammatory cytokines, acute-phase reactants and soluble adhesion molecules, and higher risk of atherosclerosis.
authors.affiliation: Humoral Immunity Institute Prof Ricardo A. Margni (IDEHU), National Research Council (CONICET) and School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), Buenos Aires, Argentina.
authors.forename: Alberto Penas
authors.initials: AP
authors.lastname: Steinhardt
authors.forename: Florencia
authors.initials: F
authors.lastname: Aranguren
authors.forename: Mariana L
authors.initials: ML
authors.lastname: Tellechea
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Gómez Rosso
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Brites
authors.forename: Maria T
authors.initials: MT
authors.lastname: Martínez-Larrad
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano-Ríos
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Frechtel
authors.forename: Mariano J
authors.initials: MJ
authors.lastname: Taverna
mesh_terms: D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016009:Chi-Square Distribution; D002784:Cholesterol / Q000097:blood; D003430:Cross-Sectional Studies; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D055105:Waist Circumference
chemical_list: D001786:Blood Glucose; D007328:Insulin; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D002097:C-Reactive Protein; D002784:Cholesterol