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...
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oai:doaj.org-article:8fe5115bd0284c0fa5572413abc0ba0e2021-11-18T08:05:37ZFunctional characterization of TLR4 +3725 G/C polymorphism and association with protection against overweight.1932-620310.1371/journal.pone.0050992https://doaj.org/article/8fe5115bd0284c0fa5572413abc0ba0e2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23239997/?tool=EBIhttps://doaj.org/toc/1932-6203Subclinical 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.Alberto Penas-SteinhardtLucía Soledad BarcosFiorella Sabrina BelforteMartha de SeredayJorge VilariñoClaudio Daniel GonzalezMaría Teresa Martínez-LarradMariana Lorena TellecheaManuel Serrano-RíosEdgardo PoskusGustavo Daniel FrechtelFederico Coluccio LeskowPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e50992 (2012) |
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Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Alberto Penas-Steinhardt Lucía Soledad Barcos Fiorella Sabrina Belforte Martha de Sereday Jorge Vilariño Claudio Daniel Gonzalez María Teresa Martínez-Larrad Mariana Lorena Tellechea Manuel Serrano-Ríos Edgardo Poskus Gustavo Daniel Frechtel Federico Coluccio Leskow Functional characterization of TLR4 +3725 G/C polymorphism and association with protection against overweight. |
| 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. |
| format |
article |
| author |
Alberto Penas-Steinhardt Lucía Soledad Barcos Fiorella Sabrina Belforte Martha de Sereday Jorge Vilariño Claudio Daniel Gonzalez María Teresa Martínez-Larrad Mariana Lorena Tellechea Manuel Serrano-Ríos Edgardo Poskus Gustavo Daniel Frechtel Federico Coluccio Leskow |
| author_facet |
Alberto Penas-Steinhardt Lucía Soledad Barcos Fiorella Sabrina Belforte Martha de Sereday Jorge Vilariño Claudio Daniel Gonzalez María Teresa Martínez-Larrad Mariana Lorena Tellechea Manuel Serrano-Ríos Edgardo Poskus Gustavo Daniel Frechtel Federico Coluccio Leskow |
| author_sort |
Alberto Penas-Steinhardt |
| 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. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/8fe5115bd0284c0fa5572413abc0ba0e |
| work_keys_str_mv |
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