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Lack of Association Between Genetic Polymorphism Of +Model ARTICLE IN PRESS J Pediatr (Rio J). 2016;xxx(xx):xxx---xxx www.jped.com.br ORIGINAL ARTICLE Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesityଝ a,1 a,∗,1 Patrícia de Araújo Pereira , António Marcos Alvim-Soares Jr. , d c Valéria Cristina Sandrim , Carla Márcia Moreira Lanna , b b Débora Cristine Souza-Costa , Vanessa de Almeida Belo , a b Jonas Jardim de Paula , José Eduardo Tanus-Santos , a a Marco Aurélio Romano-Silva , Débora Marques de Miranda a INCT de Medicina Molecular, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil b Department of Pharmacology, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil c Department of Physiology, Institute of Biologic Science, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil d Universidade Estadual Paulista (UNESP), São Paulo, SP, Brazil Received 15 July 2015; accepted 15 December 2015 KEYWORDS Abstract Single-nucleotide Objective: Obesity is a chronic disease caused by both environmental and genetic factors. polymorphisms; 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 Childhood obesity; interaction between genetic and environmental components can facilitate the choice of the Fat mass and obesity associated; most effective and specific measures for the prevention of obesity. The aim of this study was Gene; to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and AKT1; insulin resistance. AKTIP 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. ଝ Please cite this article as: Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of asso- ciation between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016. http://dx.doi.org/10.1016/j.jped.2015.12.007 ∗ Corresponding author. E-mail: [email protected] (A.M. Alvim-Soares Jr.). 1 Both Authors contributed equally to this paper. http://dx.doi.org/10.1016/j.jped.2015.12.007 0021-7557/© 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). JPED-402; No. of Pages 7 +Model ARTICLE IN PRESS 2 Pereira PA et al. 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. © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). PALAVRAS-CHAVE Falta de associac¸ão entre o polimorfismo genético do FTO, AKT1 e AKTIP e o sobrepeso e a obesidade infantis Polimorfismos de nucleotídeo único; Resumo Obesidade infantil; Objetivo: A obesidade é uma doenc¸a crônica sustentada por fatores ambientais e genéticos. Associado à massa de Estudos epidemiológicos documentaram que maior ingestão de energia e um estilo de vida gordura e à sedentário, bem como a contribuic¸ão genética, são forc¸as por trás da epidemia de obesidade. obesidade; O conhecimento sobre a interac¸ão entre os componentes genéticos e ambientais pode facilitar Gene; a escolha das medidas mais efetivas e específicas para a prevenc¸ão da obesidade. O objetivo AKT1; deste estudo foi avaliar a relac¸ão entre os genes FTO, AKT1 e AKTIP e a obesidade infantil e AKTIP resistência à insulina. Métodos: Estudo de caso-controle no qual SNPs nos genes FTO (rs99396096), AKT1 e AKTIP foram genotipados em grupos de controle e de crianc¸as obesas/acima do peso. Foram recrutadas 195 crianc¸as 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 de HOMA-IR, colesterol total, lipopro- teína de baixa densidade e triglicerídeos. Contudo, não encontramos diferenc¸as 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 crianc¸as brasileiras. São necessários estudos futuros sobre a genética da obesidade em crianc¸as brasileiras e suas interac¸ões ambientais. © 2016 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Este e´ um artigo Open Access sob uma licenc¸a CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Introduction many metabolic, mitogenic, and anti-apoptotic effects of insulin, IGF-1, and IL-3, and other growth factors and 12---14 Childhood obesity is a public health problem worldwide. cytokines. Moreover, Akt also stimulates glucose uptake 14 15 Over the past decades, rates of overweight and obesity and glycogen synthesis, as well as protein synthesis. among children have largely increased both in developed Several studies correlate insulin resistance to impairments 1 and developing countries. Obesity is a result of environ- at Akt pathway and, in certain conditions, these alterations mental factors interacting with a polygenic background; can be of genetic origin. AKT1-binding protein (AKTIP or 2 the heritability ranges from 40% to 70%. A recent meta- Ft1), located near to FTO at the same GWAS risk locus 16 regression analysis showed that heritability was higher in for obesity at chromosome 16 (16q12.2), appears to be 3 children than in adults. Long-term studies have shown another target for investigation. AKTIP, as a direct-ligand 17 that childhood obesity leads to clustering of metabolic of AKT, modulates integration signaling pathways. 4 syndrome (MetS) components, which include abdominal Energy balance is influenced by a number of variables obesity, dyslipidemia, insulin resistance, type II diabetes, such as diet, social structures, metabolic factors, mod- 5 and hypertension. It is well known that overweight and ern sedentary lifestyle, inexpensive energy-dense foods, obese children have a higher risk to become obese in and genetics. Probably, common obesity is the result of 6 adulthood. an adverse obesogenic environment and a susceptible 4 Genome-wide association studies (GWAS) identified the genotype. To date, evidence for the possible clinical ben- Fat mass and obesity associated gene (FTO) as associated efits of genetic studies for common complex diseases has 7 with human adiposity. The FTO gene is related to obesity been limited. Furthermore, the search for genetic fac- risk, especially the single nucleotide polymorphism (SNP) tors involved in obesity is a challenge, and can provide rs9939609, which has been further confirmed by others extra data to answer such a complex question. Through 8---11 independent studies in different human populations. these observations, this study aimed to investigate the sta- Due to the close relationship between diabetes and obesity, tistical association of polymorphisms in the FTO, AKT1, another interesting gene is the V-Akt murine thymoma viral and AKTIP genes with childhood obesity in Brazilian oncogene homolog 1 (AKT1), which is thought to mediate children. +Model ARTICLE IN PRESS Genetic and childhood obesity 3 Methods Caucasian and Yoruba individuals in the HapMap database were chosen. Genotyping was done with real-time poly- merase chain reaction (RT-PCR) using a 7500 Real-Time PCR Clinical data System (Applied Biosystems Inc., CA, USA), in allelic discrim- ination mode. PCR protocols were performed in accordance Parents and children were informed and signed a written ® with the TaqMan Genotyping Master Mix manufacturer’s consent about the nature and purpose of this study. All chil- instructions (Applied Biosystems, CA, USA). dren were submitted to a thorough physical examination. Height was measured using a wall-mounted stadiometer while body weight was measured through a digital scale. Statistical analysis Body mass index (BMI) was calculated using weight and height measurements according to the equation BMI = weight Allele, haplotype and genotype frequencies were com- 2 (kg)/height (cm). The BMI cut-off points adopted were pared between groups with the chi-squared test using 18 those established by the World Health Organization (WHO). the UNPHASED software (UNPHASED, v.3.0.13, Cambridge, 25 Overweight and obesity were defined as BMI greater than United Kingdom). 1,000 permutations test (post-test) was 19 +1 and +2 standard deviation, respectively. Blood pressure performed for each test in order to estimate the global was measured at least twice and the presence of hyperten- significance for all analyses and to validate the expectation- sion was defined as systolic and/or diastolic blood pressure maximization values. HAPLOVIEW 4.1 software (HAPLOVIEW, 20 above the 95th percentile. None of the children used med- v 4.1, Broad Institute, MA, USA) was used to evaluate pair- ication. wise linkage disequilibrium (LD) matrices between each SNP Lipid profile and glycemia were determined in serum to examine the LD block structure and Hardy---Weinberg 26 and plasma, respectively, with routine enzymatic commer- equilibrium (cutoff 0.05). Odds ratio and permutations cial kits (Labtest Diagnóstica, S.A., Brazil). Insulin levels were performed using UNPHASED. After Bonferroni correc- were measured using a kit (Genesis Diagnostics Products, São tion, the significance level was established at 0.0083 for Paulo, Brazil).
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