Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight
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 s...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | Artículo publishedVersion |
| Lenguaje: | Inglés |
| Publicado: |
2012
|
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_19326203_v7_n12_p_PenasSteinhardt |
| Aporte de: |
| id |
paperaa:paper_19326203_v7_n12_p_PenasSteinhardt |
|---|---|
| record_format |
dspace |
| spelling |
paperaa:paper_19326203_v7_n12_p_PenasSteinhardt2023-06-12T16:51:36Z Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight PLoS ONE 2012;7(12) 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. 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 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. 2012 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_19326203_v7_n12_p_PenasSteinhardt |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| language |
Inglés |
| orig_language_str_mv |
eng |
| topic |
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 |
| spellingShingle |
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 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. Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight |
| topic_facet |
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 |
| description |
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. |
| format |
Artículo Artículo publishedVersion |
| author |
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. |
| author_facet |
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. |
| author_sort |
Penas-Steinhardt, A. |
| title |
Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight |
| title_short |
Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight |
| title_full |
Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight |
| title_fullStr |
Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight |
| title_full_unstemmed |
Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight |
| title_sort |
functional characterization of tlr4 +3725 g/c polymorphism and association with protection against overweight |
| publishDate |
2012 |
| url |
http://hdl.handle.net/20.500.12110/paper_19326203_v7_n12_p_PenasSteinhardt |
| work_keys_str_mv |
AT penassteinhardta functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT barcosls functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT belfortefs functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT deseredaym functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT vilarinoj functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT gonzalezcd functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT martinezlarradmt functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT tellecheaml functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT serranoriosm functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT poskuse functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT frechtelgd functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight AT leskowfc functionalcharacterizationoftlr43725gcpolymorphismandassociationwithprotectionagainstoverweight |
| _version_ |
1769810354659917824 |