Functional characterization of TLR4 +3725 G/C polymorphism and association with protection against overweight.

PENAS STEINHARDT, ALBERTO; LUCIA S BARCOS ; FIORELLA SABRINA BELFORTE ; MARTHA S DE SEREDAY ; C.D. GONZALEZ ; M. T. MARTÍNEZ-LARRAD; M.L. TELLECHEA; M. SERRANO-RÍOS; POSKUS, EDGARDO; G. D, FRECHTEL; FEDERICO COLUCCIO LESKOW

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 8

1932-6203

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 activation of innate immune response. We studied two polymorphisms (+3725G/C and 11350G/C) in the 3´untranslated region (3´UTR) of TLR4 gene that may alter its translation efficiency and have potential impact on the development of 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 and 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 which causes systemic inflammation, we studied these possible effects in both, smokers and nonsmokers. The 11350G/C polymorphism was not detected in our sample. CC genotype of +3725 polymorphism was associated with lean subjects (p=0.008) and higher Adiponectin levels (p=0.021). Subjects without any NCEP/ATP III MS component were associated with this genotype as well (p=0.002). These results were strengthened in nonsmokers,in which CC genotype was associated with lean subjects (p=0.004) and compared with G carriers showed significantly lower BMI (25.53 vs. 28.60kg/m2; p=0.02), waist circumference (89.27 vs. 97.51cm; p=0.03) and higher Adiponectin levels (15.00 vs. 10.48ng/ml; p=0.02). None of these associations were found in smokers. These results would show a functional effect of +3725C variant down-regulating gene expression and a clinical impact as a protective factor against overweight, particularly in nonsmokers. Considering the role of TLR4 in inflammation, these findings would suggest that the presence of +3725C variant would prevent the emergence of chronic metabolic disorders.