Authors: Penas-Steinhardt, A.; Barcos, L.S.; Belforte, F.S.; de Sereday, M.; Vilariño, J.; Gonzalez, C.D.; Martínez-Larrad, M.T.; Tellechea, M.L.; Serrano-Ríos, M.; Poskus, E.; Frechtel, G.D.; Leskow, F.C.
Publication Date: 2012.
Subclinical low-grade systemic inflammation has been associated with obesity, insulin resistance and metabolic syndrome (MS). Recent studies have highlighted the role of gut microbiota in these disorders. The toll-like receptor 4 (TLR4) plays a key role in the innate immune response activation. We studied two polymorphisms (+3725G/C and 11350G/C) in the 3′ untranslated region (3′UTR) of the TLR4 gene that may alter its expression and their association with metabolic disorders related to systemic inflammation. We cloned the 3′UTR into a luciferase reporter system and compared wild-type 3′UTR (WT) and +3725C variant (MUT) constructs luciferase activities. MUT construct reduced the reporter gene activity by 30% compared to WT (P = 0.0001). To evaluate the association between these polymorphisms with biochemical and clinical overweight related variables, we conducted a population cross-sectional study in 966 men of Argentine general population. Considering smoking as a confounding variable that causes systemic inflammation, we studied these possible effects in both, smokers and nonsmokers. The 11350G/C polymorphism was not detected in our sample whereas the CC genotype of +3725 polymorphism was associated with lean subjects (p = 0.011) and higher Adiponectin levels (p = 0.021). Subjects without any NCEP/ATP III MS component were associated with this genotype as well (p = 0.001). These results were strengthened in nonsmokers, in which CC genotype was associated with lean subjects (p = 0.003) and compared with G carriers showed significantly lower BMI (25.53 vs. 28.60 kg/m2; p = 0.023) and waist circumference (89.27 vs. 97.51 cm; p = 0.025). None of these associations were found in smokers. These results showed that +3725C variant has a functional effect down-regulating gene expression and it could be considered as a predictive factor against overweight, particularly in nonsmokers. Considering the role of TLR4 in inflammation, these findings would suggest that the presence of +3725C variant could predict a lower prevalence of chronic metabolic disorders. © 2012 Penas-Steinhardt et al.
Keywords: adiponectin; cysteine; glycine; luciferase; messenger RNA; toll like receptor 4; 3' untranslated region; adult; Argentina; article; body mass; cross-sectional study; down regulation; enzyme activity; ethnic group; gene activity; gene expression regulation; gene frequency; gene function; genetic analysis; genetic association; genetic stability; genetic variability; genotype; heterozygote; human; inflammation; lean body weight; major clinical study; male; molecular cloning; obesity; population research; prediction; protection; regulator gene; reporter gene; single nucleotide polymorphism; smoking habit; systemic disease; toll like receptor 4 gene; waist circumference; wild type; 3' Untranslated Regions; Adiponectin; Adult; Gene Expression Regulation; Genetic Association Studies; Humans; Immunity, Innate; Insulin Resistance; Male; Metabolic Syndrome X; Obesity; Overweight; Polymorphism, Single Nucleotide; Smoking; Toll-Like Receptor 4.
Repository: Biblioteca Digital (UBA-FCEN). Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales