RESUMO
ANTECEDENTES: Tanto el gen FTO (Fat-mass and obesity-associated-gene) y el tiempo sedente se asocian a obesidad, sin embargo, se desconoce si el tiempo sedente puede modificar la predisposición genética a la obesidad. Por ende, el objetivo de este estudio fue investigar si la asociación entre el polimorfismo rs9939609 del gen FTO y marcadores de adiposidad podrían ser modificados por el tiempo sedente. MÉTODOS: Este estudio de corte transversal incluye a 409 participantes del estudio GENADIO. Los marcadores de adiposidad estudiados fueron peso corporal, índice de masa corporal (IMC), perímetro de cintura (PC) y porcentaje masa grasa. El tiempo sedente se determinó mediante acelerometría de movimiento. La interacción entre el gen FTO (rs9939609) y el tiempo sedente sobre los marcadores de adiposidad se determinó mediante análisis de regresión múltiple. RESULTADOS: Tanto la variante de riesgo del gen FTO como el tiempo sedente se asociaron a mayor peso corporal, IMC, PC y masa grasa. Sin embargo, la asociación entre tiempo sedente y marcadores de adiposidad fue mayor en personas portadoras del alelo de riesgo del gen FTO. Por cada 1 hora de incremento en tiempo sedente, el peso corporal incrementa en 1,36 kg ([95% IC: 0,27; 2,46], p = 0,015) y 2,95 kg ([95% IC: 1,24; 4,65], p = 0,001) en personas con la variante protectora (TT) versus aquellos con la variante de riesgo (AA), respectivamente. Resultados similares se encontraron para (PC). CONCLUSIÓN: La asociación entre la variante de riesgo de FTO y mayor nivel de adiposidad es más acentuada en individuos que presentan mayores niveles de sedentarismo.
BACKGROUND: The Fat-mass and obesity-associated-gene (FTO gene) and sedentary behavior time are associated with obesity. However, whether sedentary behavior time can modify the genetic predisposition to obesity in the Chilean population is unknown. Therefore, this study investigated the association between sedentary behavior, adiposity markers, and the FTO gene. METHODS: This cross-sectional study included 409 participants from the Genes, Environment, Diabetes, and Obesity (GENADIO) study. Adiposity markers studied included body weight, body mass index (BMI), waist circumference (WC), and fat mass. Sedentary behaviors were measured using accelerometers. Using multiple regression, we evaluated the interaction between sedentary behaviors and the FTO gene (rs9939609) on adiposity markers. RESULTS: Sedentary behaviors and the FTO genotype were positively associated with higher body weight, BMI, WC, and fat mass. However, the association between time of sedentary behavior and adiposity markers was higher in carriers of the risk variant for the FTO gene. For each hour of increment in sedentary behaviors, body weight increases by 1.36 kg ([95% CI: 0.27; 2.46], p = 0.015) and 2.95 kg ([95%CI: 1.24; 4.65], p = 0.001) in non-risk carriers (TT) versus risk carriers (AA), respectively. We observed similar results for WC, BMI, and body fat, but the interaction was significant only for WC. CONCLUSION: The association between sedentary behaviors and adiposity markers, especially body weight and WC, is higher in individuals who carry the risk variant of the FTO gene.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Índice de Massa Corporal , Predisposição Genética para Doença/genética , Adiposidade/genética , Circunferência da Cintura/genética , Comportamento Sedentário , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Obesidade/genética , Chile , Estudos Transversais , Fatores de Risco , Polimorfismo de Nucleotídeo Único/genética , GenótipoRESUMO
Obesity-associated protein (FTO) is an important m6A demethylase that regulates RNA methylation modification and can promote the proliferation of acute myeloid leukemia(AML) cells. FTO regulates the methylation level of AML through multiple cellular signaling pathways such as FTO/RARA/ASB2, FTO/m6A/CEBPA, and PDGFRB/ERK, and participates in the occurrence, development, treatment and prognosis of AML. At present, studies have found that a variety of inhibitors targeting FTO have shown good anti-leukemia effects, and the study of FTO will provide new ideas for the treatment of AML. This review focus on the mechanism of action of FTO in AML and the research progress of FTO inhibitors in AML.
Assuntos
Humanos , Metilação , Leucemia Mieloide Aguda/genética , Prognóstico , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismoRESUMO
A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.
Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.
Assuntos
Humanos , Masculino , Feminino , Peso Corporal/genética , Epigenômica , Genes/genética , Obesidade/genética , Índice de Massa Corporal , Expressão Gênica/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 4 de Melanocortina/genética , Melanocortinas/genética , Receptores para Leptina/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Hipotálamo/fisiopatologia , Obesidade/fisiopatologiaRESUMO
BACKGROUND@#There are only limited numbers of reviews on the association of maternal-child genetic polymorphisms and environmental and lifestyle-related chemical exposure during pregnancy with adverse fetal growth. Thus, this article aims to review: (1) the effect of associations between the above highlighted factors on adverse fetal growth and (2) recent birth cohort studies regarding environmental health risks.@*METHODS@#Based on a search of the PubMed database through August 2021, 68 epidemiological studies on gene-environment interactions, focusing on the association between environmental and lifestyle-related chemical exposure and adverse fetal growth was identified. Moreover, we also reviewed recent worldwide birth cohort studies regarding environmental health risks.@*RESULTS@#Thirty studies examined gene-smoking associations with adverse fetal growth. Sixteen maternal genes significantly modified the association between maternal smoking and adverse fetal growth. Two genes significantly related with this association were detected in infants. Moreover, the maternal genes that significantly interacted with maternal smoking during pregnancy were cytochrome P450 1A1 (CYP1A1), X-ray repair cross-complementing protein 3 (XRCC3), interleukin 6 (IL6), interleukin 1 beta (IL1B), human leukocyte antigen (HLA) DQ alpha 1 (HLA-DQA1), HLA DQ beta 1 (HLA-DQB1), and nicotinic acetylcholine receptor. Fetal genes that had significant interactions with maternal smoking during pregnancy were glutathione S-transferase theta 1 (GSTT1) and fat mass and obesity-associated protein (FTO). Thirty-eight studies examined the association between chemical exposures and adverse fetal growth. In 62 of the 68 epidemiological studies (91.2%), a significant association was found with adverse fetal growth. Across the studies, there was a wide variation in the analytical methods used, especially with respect to the genetic polymorphisms of interest, environmental and lifestyle-related chemicals examined, and the study design used to estimate the gene-environment interactions. It was also found that a consistently increasing number of European and worldwide large-scale birth cohort studies on environmental health risks have been conducted since approximately 1996.@*CONCLUSION@#There is some evidence to suggest the importance of gene-environment interactions on adverse fetal growth. The current knowledge on gene-environment interactions will help guide future studies on the combined effects of maternal-child genetic polymorphisms and exposure to environmental and lifestyle-related chemicals during pregnancy.
Assuntos
Feminino , Humanos , Gravidez , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Desenvolvimento Fetal , Interação Gene-Ambiente , Estilo de Vida , Exposição Materna/efeitos adversos , Polimorfismo GenéticoRESUMO
In the process of animal fat deposition, the proliferation and differentiation of pre-adipocytes and the change of lipid droplet content in adipocytes are regulated by a series of transcription factors and signal pathways. Although researchers have conducted in-depth studies on the transcriptional regulation mechanisms of adipogenesis, there are relatively few reports on post-transcriptional modification on mRNA levels. The modification of mRNA m6A regulated by methyltransferase, demethylase and methylation reading protein is a dynamic and reversible process, which is closely related to fat deposition in animals. Fat mass and obesity associated proteins (FTO) act as RNA demethylases that affect the expression of modified genes and play a key role in fat deposition. This article summarized the mechanism of FTO-mediated demethylation of mRNA m6A in the process of animal fat deposition, suggesting that FTO may become a target for effective treatment of obesity. Moreover, this review summarized the development of FTO inhibitors in recent years.
Assuntos
Animais , Adipócitos , Adipogenia/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Obesidade/genética , RNA Mensageiro/genéticaRESUMO
Intrauterine growth restriction (IUGR) is related to a higher risk of neonatal mortality, minor cognitive deficit, metabolic syndrome, and cardiovascular disease in adulthood. In previous studies, genetic variants in the FTO (fat mass and obesity-associated) and PPARγ (peroxisome proliferator-activated receptor-gamma) genes have been associated with metabolic disease, body mass index, and obesity among other outcomes. We studied the association of selected FTO (rs1421085, rs55682395, rs17817449, rs8043757, rs9926289, and rs9939609) and PPARγ (rs10865710, rs17036263, rs35206526, rs1801282, rs28763894, rs41516544, rs62243567, rs3856806, and rs1805151) single-nucleotide polymorphisms (SNPs) with IUGR, through a case-control study in a cohort of live births that occurred from June 1978 to May 1979 in a Brazilian city. We selected 280 IUGR cases and 256 controls for analysis. Logistic regression was used to jointly analyze the SNPs as well as factors such as maternal smoking, age, and schooling. We found that the PPARγ rs41516544 increased the risk of IUGR for male offspring (OR 27.83, 95%CI 3.65-212.32) as well as for female offspring (OR=8.94, 95%CI: 1.96-40.88). The FTO rs9939609 TA genotype resulted in a reduced susceptibility to IUGR for male offspring only (OR=0.47, 95%CI: 0.26-0.86). In conclusion, we demonstrated that PPARγ SNP had a positive effect and FTO SNP had a negative effect on IUGR occurrence, and these effects were gender-specific.
Assuntos
Humanos , Masculino , Feminino , Adulto , PPAR gama/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Brasil/epidemiologia , Índice de Massa Corporal , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Retardo do Crescimento Fetal/genética , GenótipoRESUMO
Abstract Objective: To investigate the association between the FTO gene polymorphism with obesity in Brazilian adolescents from the Northeast region. Method: This was a case-control study with adolescents aged 18 to 19 years. The case group consisted of 378 obese individuals and the control group of 378 non-obese individuals. Obesity was measured by percentage of body fat using the air displacement plethysmography technique. The study variables included data on socioeconomics, demographics, lifestyle, physical activity, waist circumference, waist-to-height ratio, and body mass index. To identify the rs9939609 polymorphism of the FTO gene, blood samples were obtained for genomic DNA extraction by the real-time PCR (Polymerase Chain Reaction) technique. Categorical variables were compared between the groups by the chi-squared test. The normality of the anthropometric measurements body mass index, waist circumference, waist-to-height ratio, and percentage of body fat was evaluated by the Shapiro-Wilk test. Comparison of the anthropometric measurements, stratified by the polymorphism genotypes, was performed by the Kruskal-Wallis test. The Hardy-Weinberg equilibrium was calculated. The significance level was set at 5%. Results: The variables gender, age, and physical activity showed significant differences between the groups (p < 0.001). The samples of obese and non-obese adolescents were in Hardy-Weinberg equilibrium (p = 0.0515). There was no significant difference between the genotypic (p = 0.719) and allelic frequencies (p = 0.812) regarding the case and control groups. When comparing the anthropometric measurements according to the genotypes (AA, AT, and TT), no significant difference was observed for body mass index (p = 0.337), waist circumference (p = 0.3473), percentage of body fat (p = 0.7096), and waist-to-height ratio (p = 0.2584). Conclusion: The excess adiposity of the study adolescents was not influenced by their genotype.
Resumo Objetivo: Investigar a relação do polimorfismo do gene FTO com obesidade em adolescentes no Nordeste brasileiro. Método: Estudo caso-controle realizado com adolescentes de 18 a 19 anos. O grupo caso foi formado por 378 indivíduos obesos e o controle por 378 não obesos. Obesidade foi medida pelo percentual de gordura corporal pela técnica de pletismografia por deslocamento de ar. Variáveis em estudo englobam dados socioeconômicos, demográficos, hábitos de vida, atividade física, circunferência da cintura, razão cintura-estatura e índice de massa corporal. Para identificação do polimorfismo rs9939609 do gene FTO foram obtidas amostras de sangue para extração do DNA genômico pela técnica de PCR em tempo real. Variáveis categóricas foram comparadas entre os grupos pelo teste qui-quadrado. Normalidade das medidas antropométricas índice de massa corporal, circunferência da cintura, razão cintura-estatura e percentual de gordura corporal foram avaliados pelo teste Shapiro-Wilk. Comparação das medidas antropométricas, estratificadas pelos genótipos do polimorfismo, foi realizada pelo teste Kruskall-Wallis. Calculou-se o equilíbrio de Hardy-Weinberg. Nível de significância adotado de 5%. Resultados: As variáveis sexo, idade e atividade física apresentaram diferenças significativas entre os grupos (p < 0,001). As amostras dos adolescentes obesos e não obesos estavam em equilíbrio de Hardy-Weinberg (p = 0,0515). Não houve diferença significante entre as frequências genotípicas (p = 0,719) e alélicas (p = 0,812) em relação aos grupos caso e controle. Quando comparadas as medidas antropométricas segundo os genótipos (AA, AT e TT), não foi observada diferença significante do índice de massa corporal (p = 0,3337), circunferência da cintura (p = 0,3473), percentual de gordura corporal (p = 0,7096) e razão cintura-estatura (p = 0,2584). Conclusão: O excesso de adiposidade dos adolescentes em estudo não foi influenciado pelo genótipo.
Assuntos
Humanos , Adolescente , Adulto Jovem , Polimorfismo de Nucleotídeo Único , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Obesidade/genética , Brasil , Índice de Massa Corporal , Estudos de Casos e Controles , GenótipoRESUMO
Resumen: Introducción: La obesidad es una enfermedad inflamatoria donde la genética determina cierto nivel de riesgo. Aun cuando existen estudios que reportan asociación entre polimorfismos de FTO (fat-mass associated gene) y adiposidad, existe limitada evidencia en población infantil chilena. Objetivo: determinar la asociación entre el polimorfismo rs9939609 del FTO y marcadores de adiposidad en población in fantil chilena. Pacientes y Método: Estudio de corte transversal incluyó 361 participantes (de 6 a 11 años; 50% niñas). Los datos clínicos y la recolección de muestras de sangre se realizaron entre marzo y junio de 2008. El polimorfismo SNP (rs9939609), del gen FTO, se determinó utilizando ADN genómico extraído de leucocitos, utilizando el Mini Kit QIAamp DNA Blood (Qiagen GmbH, Hilden, Alemania). Los marcadores de adiposidad estudiados fueron, índice de masa corporal (IMC), masa grasa, perímetro de cintura (PC) y razón cintura/talla, y se compararon ajustados por sexo, edad y estadio de Tanner. La asociación entre el polimorfismo estudiado y los marcadores de obesidad se realizó mediante análisis de regresión lineal. Resultados: Al ajustar los marcadores por sexo, edad y estadío de Tanner se observó una asociación significativa entre el polimorfismo e indicadores de adi posidad. Por cada copia extra del alelo de riesgo se encontró un aumento de 2,47 kg de peso corporal, (IC 95%: 1,39-3,55); 1,06 kg/m2 de IMC, (IC 95%: 0,56-1,54); 2,55 cm de PC, (IC 95%: 1,26-3,85) y 1,98% de masa grasa, (IC 95%: 0,78-3,19). Al convertir los marcadores de adiposidad a z-score, la razón perímetro de cintura/talla arrojó la mayor asociación con el alelo de riesgo de FTO. Conclu sión: Este estudio indica asociación entre el polimorfismo rs9939609 del gen FTO con marcadores de adiposidad general y central en población infantil en Chile.
Abstract: Introduction: Obesity is considered a chronic inflammatory disease with an important genetic component. Although several studies have reported an association between the FTO (fat-mass associated gene) and adiposity in children, there is limited evidence in the Chilean population. Objective: To deter mine the association between the polymorphism rs9939609 of the FTO gene and markers of adipo sity in Chilean children. Patients and Method: Cross-sectional study which included 361 children aged between 6 and 11 years (50% were girls). Between March and June 2008, clinical data and blood sample collection was carried out. The rs9939609 single-nucleotide polymorphism (SNP) of the FTO gene, was determined using the genomic DNA extracted from leukocytes, using the QIAamp DNA Blood Mini Kit (Qiagen GmbH, Hilden, Germany).The adiposity markers included were body mass index (BMI), waist circumference (WC), body fat, and WC/H index; which were later compared adjusted by sex, age, and Tanner stage. Linear regression analyses were conducted to detect the association between the polymorphism and obesity markers. Results: After adjusting the models by age, sex, and Tanner stage, we found a significant association between the polymorphism and markers of adiposity. For each extra copy of the risk allele, we found an increase of 2.47 kg body weight (95% CI: 1.39-3.55); 1.06 kg/m2 BMI (95% CI: 0.56-1.54); 2.55 cm WC, (95% CI: 1.26-3.85); and 1.98% body fat (95% CI: 0.78-3.19). When converting adiposity markers to z-score, we found that WC/height index shows the strongest association with the risk allele FTO. Conclusion: This study supports the association between the rs9939609 SNP of the FTO gene and overall and central adiposity markers in Chilean children.
Assuntos
Humanos , Masculino , Feminino , Criança , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adiposidade/genética , Obesidade Infantil/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Marcadores Genéticos , Modelos Lineares , Chile , Estudos Transversais , Obesidade Infantil/diagnóstico , Obesidade Infantil/patologiaRESUMO
OBJECTIVE@#To investigate the down-regulation effect of let-7b-5p on the expression of FTO in acute myeloid leukemia cell line THP-1 and inhibitory effect on THP-1 proliferation via m@*METHODS@#The acute myeloid leukemia cell line THP-1 and the normal human peripheral blood mononuclear cells (PBMNC) were selected as subjects. The expression of let-7b-5p and FTO mRNA in those cells was detected by qPCR, further the expression of FTO protein in those cells was detected by Western blot. And, the luciferase reporter gene assay was used to verify the targeting effect of let-7b-5p on FTO. Finally, THP-1 cells were transfected respectively with let-7b-5p mimic, and PBMNC with let-7b-5p inhibitor, there after the C-MYC mRNA m@*RESULTS@#Compared with PBMNC, the expression of let-7b-5p in THP-1 significantly decreased, while the expression of FTO was significantly increased (P<0.05). After transfection with let-7b-5p mimic combined with FTO 3'-UTR, the luciferase activity of transfected THP-1 cells significantly decreased, but the luciferase activity significantly increased after transfection with mutant 3'-UTR, which was significantly different from the negative control group(blank vector) (P<0.05). Let-7b-5p inhibitor down-regulated c-MYC mRNA m@*CONCLUSION@#Human acute myeloid leukemia cell line THP-1 low expresses the let-7b-5p, which regulates c-MYC expression through let-7b-5p-/FTO-/m
Assuntos
Humanos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Linhagem Celular Tumoral , Proliferação de Células , Leucemia , Leucócitos Mononucleares , MicroRNAs/genética , Transdução de Sinais , Células THP-1RESUMO
Determinar la distribución genotípica y la frecuencia alélica del polimorfismo rs17817449 del gen FTO en jóvenes chilenos y su influencia en variables antropométricas. Los 96 sujetos jóvenes (18-25 años), 43 hombres y 53 mujeres fueron evaluados utilizando genotipificación del polimorfismo rs17817449 del gen FTO en TT, TG y GG mediante polimerase chain reaction (PCR), además de una evaluación Kinenatropométrica para determinar las variables asociadas a composición corporal. Las variables fueron analizadas estadísticamente según su distribución paramétrica y el nivel de significancia estadística fue p<0,05. La distribución genotípica del polimorfismo rs17817449 de FTO en jóvenes chilenos fue: TT: 50 %; TG: 42,7 %; GG 7,3 % y la distribución alélica fue: T: 0,7105 y G: 0,2895. No se encontraron diferencias estadísticamente significativas en las variables antropométricas al analizar los participantes según modelo de dominancia del alelo G. Se determinó la distribución genotípica y la frecuencia alélica del polimorfismo rs17817449 del gen FTO en jóvenes chilenos, datos desconocidos hasta este momento. De acuerdo a nuestros resultados, no existen diferencias antropométricas entre personas con diferentes genotipos del polimorfismo rs17817449 de FTO, agrupadas según modelo de dominancia del alelo G.
The rs17817449 polymorphism of the FTO gene in young Chileans and their influence on anthropometric variables. 96 young subjects (18-25 years old), 43 men and 53 women were evaluated using genotyping of the rs17817449 polymorphism of the FTO gene in TT, TG and GG by means of polymerase chain reaction (PCR), in addition to a Kinenatropometric evaluation to determine the variables associated with body composition. The variables were analyzed statistically according to their parametric distribution and the level of statistical significance was p<0.05. The genotypic distribution of the FTO polymorphism rs17817449 in young Chileans was: TT: 50 %; TG: 42.7 %; GG 7.3 % and the allelic distribution was: T: 0.7105 and G: 0.2895. No statistically significant differences were found in the anthropometric variables when analyzing the participants according to model of dominance of the G allele. The genotypic distribution and the allelic frequency of the rs17817449 polymorphism of the gene were determined FTO in Chilean population, data unknown until now. According to our results, there are no anthropometric differences between people with different genotypes of the FTO polymorphism rs17817449, nor according to the dominance model of the G.
Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Antropometria , Polimorfismo de Nucleotídeo Único , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Variação Genética , Índice de Massa Corporal , Chile , Reação em Cadeia da Polimerase , Adiposidade/genética , Circunferência da Cintura/genética , Frequência do Gene , GenótipoRESUMO
Background: Fat-mass-associated-gene (FTO) is associated with higher energy intake and specific food preferences. Aim: To investigate the association of the FTO genotype with energy intake, macronutrient and alcohol consumption. Material and Methods: Four hundred and nine participants of the GENADIO (Genes, Environment, Diabetes and Obesity) study were included. Energy intake, macronutrient and alcohol consumption were the outcomes of interest. The association of FTO (rs9939609) genotype with these outcomes was investigated using linear regression analyses, adjusting for confounding variables. Results: After adjusting for socio-demographic factors, being a carrier of the risk allele for the FTO gene was associated with a higher energy intake (173 kcal per each extra copy of the risk variant [95% confidence intervals (CI): 45; 301], (P = 0.008). After adjusting for lifestyle factors and body mass index, the association was slightly attenuated but remained significant (144 kcal [95% CI: 14; 274], p = 0.030). Conclusions: The FTO genotype is associated with a higher energy intake.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Ingestão de Energia/genética , Consumo de Bebidas Alcoólicas/genética , Nutrientes , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Genótipo , Valores de Referência , Fatores Socioeconômicos , Exercício Físico , Modelos Lineares , Chile , Antropometria , Estudos Transversais , Fatores de Risco , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Estilo de Vida , Obesidade/genéticaRESUMO
Background: Numerous studies have identified the role of Fat-mass-associated-gene (FTO) in the development of obesity. Aim: To investigate the association of FTO gene with adiposity markers in Chilean adults. Material and Methods: 409 participants were included in this cross-sectional study. The association between FTO (rs9939609) genotype and adiposity markers was determined using linear regression analyses. Adiposity markers included were: body weight, body mass index, fat mass, waist circumference, hip circumference and waist/hip ratio. Results: A fully adjusted model showed a significant association between FTO genotype and body weight (2.16 kg per each extra copy of the risk allele [95% confidence intervals (CI): 0.45 to 3.87], p = 0.014), body mass index (0.61 kg.m-2 [95% CI: 0.12 to 1.20], p = 0.050) and fat mass (1.14% [95% CI: 0.39 to 1.89], p = 0.010). The greater magnitude of association was found between the FTO gene and fat mass when the outcomes were standardized to z-score. Conclusions: This study confirms an association between the FTO gene and adiposity markers in Chilean adults, which is independent of major confounding factors.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Adiposidade/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Genótipo , Obesidade/genética , Valores de Referência , Fatores Socioeconômicos , Marcadores Genéticos , Modelos Lineares , Chile/etnologia , Antropometria , Reação em Cadeia da Polimerase , Estudos Transversais , Fatores de Risco , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Alelos , Adiposidade/etnologia , Estilo de Vida , Obesidade/etnologiaRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.
Assuntos
Animais , Masculino , Coelhos , Peptídeos/farmacologia , Peçonhas/farmacologia , Substâncias Protetoras/farmacologia , Fígado Gorduroso/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Dioxigenase FTO Dependente de alfa-Cetoglutarato/efeitos dos fármacos , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Técnicas In Vitro , Regulação da Expressão Gênica/efeitos dos fármacos , Morfolinas/metabolismo , Cromonas/metabolismo , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Fígado Gorduroso/patologia , Dieta Hiperlipídica , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Exenatida , Insulina/sangue , Malondialdeído/análise , Obesidade/metabolismoRESUMO
ABSTRACT Objective Gestational diabetes mellitus (GDM) is a metabolic disorder that shares pathophysiologic features with type 2 diabetes mellitus. The aim of this study was to investigate the association of the polymorphisms fat mass and obesity-associated (FTO) rs1421085, leptin receptor (LEPR) rs1137100, rs1137101, peroxisome proliferator-activated receptor gamma (PPARg) rs1801282, and transcription factor 7-like 2 (TCF7L2) rs7901695 with GDM. Subjects and methods 252 unrelated Euro-Brazilian pregnant women were classified into two groups according to the 2015 criteria of the American and Brazilian Diabetes Association: healthy pregnant women (n = 125) and pregnant women with GDM (n = 127), matched by age. The polymorphisms were genotyped using fluorescent probes (TaqMan®). Results All groups were in Hardy-Weinberg equilibrium. The genotype and allele frequencies of the studied polymorphisms did not show significant differences between the groups (P > 0.05). In the healthy and GDM groups, the C allele frequencies (95% CI) of the FTO rs1421085 polymorphism were 36.8% [31-43%] and 35.0% [29-41%]; the G allele frequencies (95% CI) of the LEPR rs1137100 polymorphism were 24.8% [19-30%] and 22.8% [18-28%]; the G allele frequencies (95% CI) of the LEPR rs1137101 polymorphism were 43.6% [37-50%] and 42.9% [37-49%]; the G allele frequencies (95% CI) of the PPARg rs1801282 polymorphism were 7.6% [4-11%] and 8.3% [5-12%]; and the C allele frequencies (95% CI) of the TCF7L2 rs7901695 polymorphism were 33.6% [28-39%] and 39.0% [33-45%], respectively. Conclusion The studied polymorphisms were not associated with GDM in a Brazilian population.
Assuntos
Humanos , Feminino , Adulto , Polimorfismo Genético/genética , Diabetes Gestacional/genética , PPAR gama/genética , Diabetes Mellitus Tipo 2/genética , Receptores para Leptina/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Brasil , Estudos de Casos e Controles , Antropometria , Estudos Transversais , Fatores de Risco , Análise de Variância , Diabetes Gestacional/etnologia , Estatísticas não Paramétricas , Diabetes Mellitus Tipo 2/etnologia , Estudos de Associação Genética , Reação em Cadeia da Polimerase em Tempo Real , Frequência do Gene , Genótipo , Obesidade/genéticaRESUMO
Abstract Objective: To determine the association between overweight/obesity in schoolchildren with FTO rs9939609 polymorphism (fatmass and obesity associated) and family history of obesity. Methods: Cross-sectional study comprising a sample of 406 children aged 7-17 years in a city in southern Brazil. Overweight/obesity in schoolchildren was assessed by body mass index (BMI), and family history of obesity was self-reported by parents. Polymorphism genotyping was performed by real time PCR (polymerase chain reaction). The association between the nutritional status of schoolchildren with the presence of family obesity, stratified by polymorphism genotypes (AA [at-risk for obesity], AT, and TT), was assessed by prevalence ratio values (PR) through Poisson regression. Results: Among schoolchildren with the AA genotype, 57.4% had overweight/obesity; the percentage was lower for the AT and TT genotypes (33.1% and 28.9%, respectively). Overweight/obesity in schoolchildren was associated with a family history of obesity, especially among children with the AA genotype. The prevalence was higher among those with an obese mother (PR: 1.28; p < 0.001), obese maternal or paternal grandmother (PR: 1.22; p = 0.047), and obese paternal grandfather (PR: 1.32; p < 0.001). Conclusions: There is an association between the AA genotype of rs9939609 polymorphism and BMI among schoolchildren. The association between overweight/obesity in schoolchildren with a family history of obesity was found mainly among students with the AA genotype.
Resumo Objetivo Verificar se existe relação entre o sobrepeso/obesidade de escolares com o polimorfismo rs9939609, do gene FTO (fat mass and obesity associated), e com o histórico familiar de obesidade. Métodos Estudo transversal composto por uma amostra de 406 escolares, de sete a 17 anos, de um município do sul do Brasil. O sobrepeso/obesidade dos escolares foi avaliado(a) por meio do índice de massa corporal (IMC) e o histórico familiar de obesidade por questões autorreferidas pelos pais. A genotipagem do polimorfismo foi feita por PCR (polymerase chain reaction) em tempo real. A associação entre o estado nutricional dos escolares com a presença de obesidade familiar, estratificada pelos genótipos do polimorfismo (AA - risco para obesidade, AT e TT), foi avaliada pelos valores de razão de prevalência (RP), por meio da regressão de Poisson. Resultados Entre os escolares com o genótipo AA, 57,4% apresentaram sobrepeso/obesidade; para os genótipos TT e AT, o percentual é inferior (33,1% e 28,9%, respectivamente). O sobrepeso/obesidade do escolar associou-se com o histórico familiar de obesidade, principalmente entre os escolares portadores do genótipo AA, foi superior entre os que apresentam mãe obesa (RP: 1,28; p < 0,001), avó materna e paterna obesas (RP: 1,22; p = 0,047) e avô paterno obeso (RP: 1,32; p < 0,001). Conclusões Há relação entre o genótipo AA, do polimorfismo rs9939609, com o IMC dos escolares avaliados. A relação entre sobrepeso/obesidade do escolar com o histórico familiar de obesidade foi encontrada, principalmente, entre os escolares com o genótipo AA.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Linhagem , Polimorfismo Genético/genética , Sobrepeso/genética , Obesidade Infantil/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Índice de Massa Corporal , Estado Nutricional/genética , Estudos Transversais , Predisposição Genética para Doença/genética , Estudos de Associação GenéticaRESUMO
Abstract Objective: Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. Methods: This was a case-control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. Results: As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. Conclusion: The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.
Resumo Objetivo A obesidade é uma doença crônica sustentada por fatores ambientais e genéticos. Estudos epidemiológicos documentaram que maior ingestão de energia e um estilo de vida sedentário, bem como a contribuição genética, são forças por trás da epidemia de obesidade. O conhecimento sobre a interação entre os componentes genéticos e ambientais pode facilitar a escolha das medidas mais efetivas e específicas para a prevenção da obesidade. O objetivo deste estudo foi avaliar a relação entre os genes associado à massa de gordura e à obesidade (FTO), homólogo 1 do oncogene viral v-akt de timoma murino (AKT1) e de ligação AKT1 (AKTIP) e a obesidade infantil e a resistência à insulina. Métodos Estudo de caso-controle no qual os polimorfismos de nucleotídeo simples (SNPs) nos genes FTO (rs99396096), AKT1 e AKTIP foram genotipados em grupos de controle e de crianças obesas/acima do peso. Foram recrutadas 195 crianças obesas/acima do peso e 153 indivíduos controle. Resultados Como esperado, os indivíduos do grupo obeso/acima do peso apresentaram maior índice de massa corporal, maior glicemia de jejum, índice do modelo de avaliação de homeostase (HOMA-IR), colesterol total, lipoproteína de baixa densidade e triglicerídeos. Contudo, não encontramos diferenças significativas no genótipo de polimorfismos gênicos ou nas frequências alélicas. Conclusão Nossos resultados sugerem que os polimorfismos AKT1, FTO e AKTIP não estavam associados à obesidade/sobrepeso em crianças brasileiras. São necessários estudos futuros sobre a genética da obesidade em crianças brasileiras e suas interações ambientais.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Proteínas Adaptadoras de Transdução de Sinal/genética , Sobrepeso/genética , Proteínas Reguladoras de Apoptose/genética , Obesidade Infantil/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Brasil/etnologia , Resistência à Insulina , Estudos de Casos e Controles , Polimorfismo de Nucleotídeo Único , Frequência do Gene/genéticaRESUMO
Obesity is a great risk factor for type 2 diabetes and certain types of cancer, which become a major burden for public health worldwide. As a classic complex disease, obesity is regarded as the interaction of genetic and environmental factors. However, it is controversial which of these two factors have greater effect on obesity. Several genetic loci have recently been reported to contribute to the development of obesity reported in genome-wide association study (GWAS) these years. GWAS play an important role in complex disease research and explore the potential effect of genetic variance. To further understand the genetic influence on obesity risk, we reviewed and collected articles on Pubmed for genes that reported in recent GWAS. We summarized the publications in GWAS and found 49 candidate genes, which were strongly suggested to relate to obesity risk in human. Despite the findings of this and other similar, contemporary research projects, much of the single nucleotide polymorphism details and underlying mechanism in this field of study remains, to a great extent, unknown. As a result, future studies are needed for obesity risk in human beings.
Assuntos
Humanos , Aldose-Cetose Isomerases , Genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Fator Neurotrófico Derivado do Encéfalo , Genética , Estudo de Associação Genômica Ampla , Obesidade , Genética , Polimorfismo de Nucleotídeo Único , Proteínas , GenéticaRESUMO
Recent studies have unequivocally established the link between FTO and obesity. FTO was biochemically shown to belong to the AlkB-like family DNA/RNA demethylase. However, FTO differs from other AlkB members in that it has unique substrate specificity and contains an extended C-terminus with unknown functions. Insight into the substrate selection mechanism and a functional clue to the C-terminus of FTO were gained from recent structural and biochemical studies. These data would be valuable to design FTO-specific inhibitors that can be potentially translated into therapeutic agents for treatment of obesity or obesity-related diseases.
Assuntos
Animais , Humanos , Homólogo AlkB 1 da Histona H2a Dioxigenase , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Motivos de Aminoácidos , Domínio Catalítico , DNA , Metabolismo , Enzimas Reparadoras do DNA , Metabolismo , Metilação , Obesidade , Genética , Proteínas , Classificação , Genética , RNA , Metabolismo , Especificidade por SubstratoRESUMO
<p><b>BACKGROUND</b>Genome-wide association studies for type 2 diabetes mellitus (T2DM) identified FTO gene as a locus conferring increased risk for common obesity in many populations with European ancestry. However, the involvement of FTO gene in obesity or T2DM related metabolic traits has not been consistently established in Chinese populations. The objective of this study was to investigate the association of FTO genetic polymorphisms with metabolic syndrome (MetS) in Han Chinese.</p><p><b>METHODS</b>We tested 41 FTO single nucleotide polymorphisms (SNPs) for association between FTO and MetS-related traits. There were a total of 236 unrelated subjects (108 cases and 128 controls), grouped according to the International Diabetes Federation (IDF) criteria.</p><p><b>RESULTS</b>Of the 41 SNPs examined, only SNP rs8047395 exhibited statistical significance (P = 0.026) under a recessive model, after Bonferroni adjustment for multiple testing (OR 1.64, 95%CI 1.11-2.42; P = 0.014). The common distributions of this polymorphism among Chinese--with a minor allele frequency (MAF) of 36% in the control group versus 48% in the MetS group--greatly improved our test power in a relatively small sample size for an association study. Previously identified obesity- (or T2DM-) associated FTO SNPs were less common in Han Chinese and were not associated with MetS in this study. No significant associations were found between our FTO SNPs and any endophenotypes of MetS.</p><p><b>CONCLUSIONS</b>A more common risk-conferring variant of FTO for MetS was identified in Han Chinese. Our study substantiated that genetic variations in FTO locus are involved in the pathogenesis of MetS.</p>
Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Povo Asiático , Predisposição Genética para Doença , Genética , Variação Genética , Genética , Genótipo , Haplótipos , Genética , Síndrome Metabólica , Genética , Polimorfismo de Nucleotídeo Único , Genética , Proteínas , GenéticaRESUMO
<p><b>OBJECTIVE</b>To study the association of rs9939609 polymorphism of the fat mass and obesity associated gene (FTO) with overweight or obesity in Hazakh children.</p><p><b>METHODS</b>PCR-restriction fragment length polymorphism was used to determine the rs9939609 polymorphism in 141 patients with overweight or obesity and 138 healthy controls. Height and weight were measured for body mass index (BMI). Serum lipid levels including total cholesterol, triglyceride, high-density and low-density lipoprotein cholesterol, blood pressure, plasma glucose levels, and plasma insulin were also determined.</p><p><b>RESULTS</b>The genotype distributions of both groups were in the Hardy-Weinberg equilibrium. The frequencies of AA, AT and TT were 0.071, 0.511 and 0.418 in the overweight or obesity group, and 0.029, 0.428 and 0.543 in the controls (Chi-square = 5.74, P= 0.057). However, the frequency of AA+ AT genotype in case group (0.582, 82/141) was higher than that in the controls (0.457, 63/138)(Chi-square = 4.368, P= 0.037). The A allele frequency in the case group (0.326) was higher than that in the controls (0.243) (Chi-square = 4.772, P= 0.029). In both groups, the plasma glucose levels of individuals with AA+ AT genotype (4.88± 0.51 mol/L) was higher than those with TT genotypes (4.68± 0.56 mol/L)(P= 0.026). Logistic regression analysis showed that the A allele of the FTO gene was an independent risk factor for overweight or obesity (OR= 0.527; 95%CI: 0.319-0.869).</p><p><b>CONCLUSION</b>The A allele of the fat mass and obesity associated gene might be a risk factor of overweight or obesity in Hazakh children in Xinjiang.</p>