Artículo

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" (2012) PLoS ONE. 7(12)
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Abstract:

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.

Registro:

Documento: Artículo
Título:Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight
Autor: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.
Filiación:Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-UBA y Cátedra de Inmunología - Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
División Endocrinología, Hospital de Clínicas, Universidad de Buenos Aires (UBA), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Ciudad Autónoma de Buenos Aires, Argentina
Laboratorio de Biologia Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Servicio de Endocrinología, Hospital Fiorito, Buenos Aires, Argentina
Cardiología Clínica, Instituto FLENI, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Departmento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
División Genética, Hospital de Clínicas, Universidad de Buenos Aires (UBA), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Departamento de Ciencias Básicas, Universidad Nacional de Lujan, Luján, Buenos Aires, Argentina
Palabras clave: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
Año:2012
Volumen:7
Número:12
DOI: http://dx.doi.org/10.1371/journal.pone.0050992
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CAS:adiponectin, 283182-39-8; cysteine, 4371-52-2, 52-89-1, 52-90-4; glycine, 56-40-6, 6000-43-7, 6000-44-8; toll like receptor 4, 203811-83-0; 3' Untranslated Regions; Adiponectin; TLR4 protein, human; Toll-Like Receptor 4
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_19326203_v7_n12_p_PenasSteinhardt.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v7_n12_p_PenasSteinhardt

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Citas:

---------- APA ----------
Penas-Steinhardt, A., Barcos, L.S., Belforte, F.S., de Sereday, M., Vilariño, J., Gonzalez, C.D., Martínez-Larrad, M.T.,..., Leskow, F.C. (2012) . Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight. PLoS ONE, 7(12).
http://dx.doi.org/10.1371/journal.pone.0050992
---------- CHICAGO ----------
Penas-Steinhardt, A., Barcos, L.S., Belforte, F.S., de Sereday, M., Vilariño, J., Gonzalez, C.D., et al. "Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight" . PLoS ONE 7, no. 12 (2012).
http://dx.doi.org/10.1371/journal.pone.0050992
---------- MLA ----------
Penas-Steinhardt, A., Barcos, L.S., Belforte, F.S., de Sereday, M., Vilariño, J., Gonzalez, C.D., et al. "Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight" . PLoS ONE, vol. 7, no. 12, 2012.
http://dx.doi.org/10.1371/journal.pone.0050992
---------- VANCOUVER ----------
Penas-Steinhardt, A., Barcos, L.S., Belforte, F.S., de Sereday, M., Vilariño, J., Gonzalez, C.D., et al. Functional Characterization of TLR4 +3725 G/C Polymorphism and Association with Protection against Overweight. PLoS ONE. 2012;7(12).
http://dx.doi.org/10.1371/journal.pone.0050992