Acessibilidade / Reportar erro

Association between the FTO gene polymorphism and obesity in Brazilian adolescents from the Northeast region Please cite this article as: Rodrigues LS, Santos AM, Lima MI, Simões VM, Pereira SR. Association between the FTO gene polymorphism and obesity in Brazilian adolescents from the Northeast region. J Pediatr (Rio J). 2020;96:630-7. , ☆☆ ☆☆ Study conducted at Universidade Federal do Maranhão, São Luís, MA, Brazil.

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.

KEYWORDS
Cohort; Body fat; rs9939609 Polymorphism

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.

PALAVRAS-CHAVE
Coorte; Gordura corporal; Polimorfismo rs9939609

Introduction

Obesity, characterized by an excessive accumulation of body fat, brings complications that can be often observed in increasingly younger individuals. Some factors are related to this picture, among them environmental factors, the individual's lifestyle, differentiated diet, and environmental contaminants that can act as endocrine disruptors. 11 Ribeiro CM [Dissertação] Investigação da atividade do fluoreno, naftaleno, nonilfenol e procimidona sobre a adipogênese em cultura de células. Brasília: Universidade de Brasília; 2015.

The adolescents' social conditions are defined according to the environment where they live. 22 Teixeira F, Mascarenhas LP, Suzuki CS, Smouter L, Novello D. Prevalência de fatores antropométricos e bioquímicos sobre o estado nutricional de adolescentes. RBONE. 2018;12:S1067-77. In this sense, the diet at this stage is highly caloric, with ingestion of ultra-processed products, in addition to inadequate life habits, such as sedentary lifestyle and excessive use of electronic equipment, which are aspects that contribute to the development of obesity. 33 Chae SM, Yeo JY, Hwang JH, Lee JH, Lim J, Kwon I. Weight control in adolescents: focus groups with Korean adolescents and their teachers. J Pediatr Nurs. 2017;33:4-9. Additionally, the genetic makeup of the individual may also contribute to the onset of obesity, especially when associated with an inadequate lifestyle. 44 Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016;92:521-7.

Obesity contributes to the onset of non-communicable chronic diseases (NCCDs). 22 Teixeira F, Mascarenhas LP, Suzuki CS, Smouter L, Novello D. Prevalência de fatores antropométricos e bioquímicos sobre o estado nutricional de adolescentes. RBONE. 2018;12:S1067-77. According to Afmanand Müller, 55 Afman L, Müller M. Nutrigenomics: from molecular nutrition to prevention of disease. J Acad Nutr Diet. 2006;106:569-76. the NCCDs, such as type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), and cardiovascular diseases (CVDs),result from these associations of environmental and genetic factors, interfering in people's lives when they are obese or overweight.

Approximately 70% of obese children and adolescents tend to become obese adults as well. 66 Reilly JJ. Childhood obesity: an overview. Child Soc. 2007;21:390-6. Excess weight is associated with a gradual increase in the risk of morbidity and mortality in adulthood, since obesity is one of the risk factors for noncommunicable diseases and disorders, being the main causes of death in adults.

This can lead to an increased risk of premature death and disability in adult life, as in Brazil, among adolescents (10-19 years), at least one-fifth had excess weight and 4.9% were obese, with higher indices in the male population and in the age group of 10-11 years old. 77 Instituto Brasileiro de Geografia e Estatística. Pesquisa de Orçamentos Familiares 2008-2009: antropometria e estado nutricional de crianças, adolescentes e adultos no Brasil. IBGE, Rio de Janeiro. 2010. Available from: https://biblioteca.ibge.gov.br/visualizacao/livros/liv45419.pdf [cited 28.01.19].
https://biblioteca.ibge.gov.br/visualiza...

From the genetic point of view, different polymorphisms have been described in the literature as being associated with obesity. 88 Jesus ÍC, Alle LF, Percegona CG, Purim KS, Leite N. Relação entre polimorfismos genéticos, lipólise, metabolismo de lipídeos e exercícios aeróbios. Pensar a Prática. 2016;19. Available from: https://www.revistas.ufg.br/fef/article/view/37232 [cited 2.07.19].
https://www.revistas.ufg.br/fef/article/...
Among these, the fat mass and obesity-associated gene (FTO) has single-nucleotide polymorphisms (SNPs) associated with the metabolism alteration process and, therefore, their presence has a direct association with the status of obesity, overweight, and other pathologies. 99 Phani NM, Vohra M, Rajesh S, Adhikari P, Nagri SK, D'Souza SC, et al. Implications of critical PPARγ2, ADIPOQ and FTO gene polymorphisms in type 2 diabetes and obesity-mediated susceptibility to type 2 diabetes in an Indian population. Mol Genet Genomics. 2016;291:193-204.

The most often investigated FTO gene polymorphism that is associated with obesity is rs9939609, characterized by the substitution of T by A in intron 1. Studies indicate that individuals who are homozygous for the risk allele (A allele) are approximately 3 kg heavier or more, and have a 1.7-fold increased risk of being obese when compared to those with homozygotes for the T allele. 1010 Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889-94. Hunt et al. 1111 Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP, et al. Association of the FTO gene with BMI. Obesity (Silver Spring). 2008;16:902-4. demonstrated that this SNP is associated with an increased risk of adult individuals developing obesity and other NCCDs.

In Brazil, Silva et al. 1212 Silva CF, Zandoná MR, Vitolo MR, Campagnolo PD, Rotta LN, Almeida S, et al. Association between a frequent variant of the FTO gene and anthropometric phenotypes in Brazilian children. BMC Med Genet. 2013;14:34. carried out a study with children and adolescents from Rio Grande do Sul, with a sample of 348 children followed from birth to 8 years of age, and another one consisting of 615 children and adolescents from 4 to 18 years of age. The authors observed that individuals with the A/A genotype had a higher Z-score for body mass index (BMI), abdominal circumference, and skinfolds. However, Souza et al. 1313 Souza NS, Melo ME, Fujiwara CT, Reinhardt HL, Santos A, Cercato C, et al. rs9939609 in the FTO gene is not related to obesity and worst metabolic profile in a cohort of obese Brazilian children and adolescents. Obesity. 2011;19:S1-234. carried out a study with adults and children, also in Brazil, and observed the absence of association between the FTO gene and the anthropometric measures used in the comparisons.

It is evident that, for the most part, the studies that associate FTO gene polymorphisms and obesity were carried out with adult populations and in European and or Asian countries or in Brazilian regions predominantly of European descent, where populations are genetically more homogeneous when compared those of the Latin American countries, which are typically mixed-race. 1414 Ramos CF, Magna LA, Mello MP, Silva R, Moura-Neto RS. Genetic variation and relationships at six VNTR loci in two distinct sample populations in Brazil. Ann Hum Biol. 2004;31:660-8. Therefore, very often the results are not necessarily the same in different ethnic groups or groups organized by age range.

Thus, the aim of this study was to investigate the association of a polymorphism in the FTO gene with obesity in adolescents from the municipality of São Luís, Maranhão, Brazil.

Methods

Study type

This was a case-control study with adolescents (18 to 19 years) from the RPS Cohort of São Luís, Maranhão. The RPS cohort encompasses the cities of Ribeirão Preto, state of São Paulo; Pelotas, state of Rio Grande do Sul; and São Luís, state of Maranhão, whose main objective was to evaluate the health of individuals born in 1997 and to monitor their health until adulthood. For that purpose, data were collected periodically on breastfeeding, home stimulation, mental disorders, violence, nutrition, body composition, sleep, physical activity, and genetic factors, among others.

Study population and sample

The study population consisted of 2515 adolescents. Adolescents without information on the main variables (percentage of fat, weight, height, gender, and age) were excluded from the study. Therefore, the population consisted of 2382 adolescents.

The sample size was calculated considering a 95% confidence level, and a power of 80%; the odds ratio (OR) was estimated a priori at 2.0, with a frequency of 16% 1010 Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889-94. for the rs9939609 SNP of the FTO gene in individuals homozygous for the risk allele (A) and with a ratio of one case to one control. Thus, 682 adolescents were necessary, i.e., 341 cases and 341 controls.

Adolescents with a percentage of body fat (%BF) > 25% (boys) and >30% (girls) were defined as obese (cases), totaling 629 adolescents. The controls comprised girls with %BF ≤ 30% and boys with %BF ≤ 25% (n = 1753). In both groups, the adolescents were randomly selected considering the minimum sample size of each group, and all adolescents included were eligible.

The study included 782 adolescents, but there was no amplification in the sample of 26 adolescents, who were excluded from the study. Thus, the final sample consisted of 756 adolescents, 378 in the non-obese group (control) and 378 of the obese group (case).

Socioeconomic and demographic data, life habits

The assessed socioeconomic and demographic variables were as follows: age, gender, family income, level of schooling, ethnicity/skin color, number of people living in the household, and the Brazilian Economic Classification Criteria, marital status, separated or divorced parents, occupation, and smoking status. This information was obtained through a structured interview, according to the standardized questionnaires of the RPS Cohort.

The Mini International Neuropsychiatric Interview (M.I.N.I.) - Brazilian version 5.0.0 - DSM IVis an interview focused on the diagnosis of mental disorders such as the antisocial personality and risk of suicide; however, only information related to alcohol consumption was used. 1515 Amorim P. Mini International Neuropsychiatric Interview (MINI): validação de entrevista breve para diagnóstico de transtornos mentais. Rev Bras Psiquiatr. 2000;22:106-15. When asked about how frequently they consumed drinks containing alcohol, the present study considered as "no" for those who answered "never" and "yes" for those who said they consumed alcohol "once or more than once a week."

The physical activity level was evaluated through the 24-h Physical Activity Recall, created from the Self-Administered Physical Activity Checklist (SAPAC), 1616 Sallis JF, Strikmiller PK, Harsha DW, Feldman HA, Ehlinger S, Stone EJ, et al. Validation of interviewer- and self-administered physical activity checklists for fifth grade students. Med Sci Sports Exerc. 1996;28:840-51. classified as sedentary, low, moderate, or high. 1717 Benedetti TR, Antunes PD, Rodriguez-Añez CR, Mazo GZ, Petroski EL. Reprodutibilidade e validade do Questionário Internacional de Atividade Física (IPAQ) em homens idosos. Rev Bras Med Esporte. 2007;13:11-6.

Anthropometric and nutritional assessment

Weight measurements (in kg) were performed using a Filizola® (Filizola, SP, Brazil) scale coupled to an air displacement plethysmography (ADP) system. The participants were asked to stand barefoot, standing upright in the center of the scale, wearing the least possible clothing, head oriented in the horizontal Frankfurt plane and wearing no accessories, to undergo the measurement of height in centimeters, with the aid of an Alturexata® (Alturexata, MG, Brazil) portable stadiometer. Based on these data, the BMI was calculated by the ratio: body weight (kg)/height (m2). Measurements of waist circumference (WC) were obtained, consisting of the measurement (in cm) at the midpoint between the iliac crest and the last rib. Each participant was measured twice, and the final result was the average of the two measurements.

The participants' proportion of central fat by height was evaluated through the waist-to-height ratio (WHtR), calculated by dividing the waist circumference (cm) by height (cm). The points were determined according to Ashwell and Hsieh, 1818 Ashwell M, Hsieh SD. Six reasons why the waist-to-height ratio is a rapid and effective global indicator for health risks of obesity and how its use could simplify the international public health message on obesity. Int J Food Sci Nutr. 2005;56:303-7. indicated for adolescents of both genders, considering values below 0.50 to be adequate.

The nutritional status of the adolescents was evaluated by the BMI, adopting as the classification criteria the values for age and gender and the respective cutoff points proposed by the World Health Organization 1919 WHO, World Health Organization. Growth reference 5-19 years; 2007. Available from: http://www.who.int/growthref/who2007_bmi_for_age/en/ [accessed 04.01.18].
http://www.who.int/growthref/who2007_bmi...
for individuals aged 10.0-19.0 years; for young individuals older than 19.0 years, the World Health Organization classification was followed.2020 WHO, World Health Organization. BMI classification. 2006. Available from: http://apps.who.int/bmi/index.jsp?introPage=intro_3.html [accessed 03.03.18]
http://apps.who.int/bmi/index.jsp?introP...

The evaluation of total body fat was performed using the ADP method in the COSMED Bod Pod® (Teprel, Porto, Portugal) gold standard device. The %BF was estimated using Siri's equation. 2121 Siri WE. Body composition from fluid spaces and density: analysis of methods. Tech Meas Body Compos. 1961;61:223-44. According to the classification by Williams et al., 2222 Williams DP, Going SB, Lohman TG, Harsha DW, Snnivasan SR, Webber LS, et al. Body fatness and risk for elevated blood pressure, total cholesterol, and serum lipoprotein ratios in children and adolescents. Am J Public Health. 1992;:82. boys with a %BF > 25% and girls > 30% were considered as having excess weight.

FTO gene polymorphism

Samples of 5 mL of whole blood were collected from the cubital vein and stored under refrigeration. Genomic DNA was extracted using the DNA Blood Mini Kit (Qiagen, CA, United States) using a QIA cube automated extractor (Qiagen, CA, United States), according to the manufacturer's recommendations. Then, they were stored in a freezer at −20 °C for an indeterminate period in order to avoid possible loss of material or contamination.

A NanoDrop spectrophotometer (Termo Scientific, CA, United States), was used for the quantification of the extracted DNA, according to the manufacturer's instructions.

The analysis of the rs9939609 SNP of the FTO gene was performed using the rhAmp™ SNP Genotyping System (Integrated DNA Technologies, IA, United States) assay on a 7500 Fast System real-time PCR system (Applied Biosystems, CA, United States). The reagents were purchased commercially and used according to the manufacturer's standards.

Statistical analysis

The statistical analysis was performed using the statistical software STATA (Stata Statistical Software: Release 14. College Station, TX, United States). The normality of the anthropometric measures (BMI, WC, WHtR, and %BF) was evaluated by the Shapiro-Wilk test. The study variables in the case group were compared with those in the control group, using the chi-squared test.

The Hardy-Weinberg equilibrium was calculated for the genetic data. 2323 Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505-14. The Kruskal-Wallis test was used to compare the means of anthropometric measures stratified by the different genotypes of the rS9939609 polymorphism of the FTO gene. In all tests, the significance level was set at 5%.

Ethical considerations

The study was approved by the Research Ethics Committee of Hospital Universitário da Universidade Federal do Maranhão (No. 1,302,489), in accordance with national health council Resolution No. 466/2012 and CNS Operational Rule No. 001 of 2013.

Results

The total sample consisted of 461 girls and 297 boys, with a mean age of 18.34 years. The case group was characterized by 80.95% female subjects; 61.64% were aged 18 years or younger; 61.33% were mixed-race; 95.77% were single; 71.43% were in high school or college/university; 85.45% did not work; 26.46% had a family income of one to two minimum wages; 52.91% had non-separated parents; 65.87% were classified as belonging to social class B. Regarding lifestyle, 60.32% were sedentary, 96.03% were non-smokers, and 58.47%% did not consume alcoholic beverages (Table 1).

Table 1
Socioeconomic, demographic, and lifestyle characteristics of participants from the Ribeirão Preto, Pelotas, and São Luís, (RPS) Cohort of São Luís, Maranhão, Brazil, 2019.

In the control group, 58.99% of the individuals were males; 70.63% were aged 18 years; 62.43% declared themselves as mixed-race; 96.03% were single; 64.81% of adolescents had finished high school or were attending college/university; 85.45% did not work; 29.89% had a family income of one to two minimum wages in the month prior to the interview; 51.06% had separated parents, and 64.19% were in social class B. Regarding lifestyle, 49.47% were sedentary, 97.07% were nonsmokers, and 57.60% did not drink alcohol. Only the variables gender, age, and physical activity showed statistically significant differences between the groups (p < 0.001; Table 1).

The case and the control groups were in Hardy-Weinberg equilibrium (p = 0.0515). The distribution of the rs9939609 polymorphism was not statistically different in relation to the genotypic (p = 0.719) and allelic frequencies (p = 0.812; Table 2).

Table 2
Genotypic and allelic frequencies of the rS9939609 polymorphism of the FTO gene in the Ribeirão Preto, Pelotas, and São Luís (RPS) Cohort of São Luís, Maranhão, Brazil, 2019.

Regarding the anthropometric measures of the total sample according to the adolescents' genotype, there was no statistically significant difference between the means of BMI (p = 0.337), WC (p = 0.343), %BF (p = 0.7096), and WHtR (p = 0.2584) when comparing the different genotypes (Table 3).

Table 3
Comparison between the means of the anthropometric measures and genotype in the total sample of adolescents of the Ribeirão Preto, Pelotas, and São Luís (RPS) Cohort of São Luís, Maranhão, Brazil, 2019 (n = 756).

For comparison purposes, results from studies evaluating the association between obesity and the rs9939609 polymorphism of FTO gene are shown. BMI or dual-energy X-ray absorptiometry (DXA) were used as the criterion to define obesity. Different prevalence rates of obesity were observed, as well as the allelic (AF) and genomic (GF) frequencies (Table 4).

In this study, the GF of the TT gene was higher than the frequency shown in the studies by Pereira et al. 44 Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016;92:521-7. and Reuter et al., 2424 Reuter CP, Burgos MS, Bernhard JC, Tornquist D, Klinger EI, Borges TS, et al. Association between overweight andobesity in schoolchildren with rs9939609 polymorphism (FTO) and family history for obesity. J Pediatr. 2016;92:493-8. but lower than that of the studies by Flores et al. 2525 Flores K, Garcia O, Caamaño MC, Ronquillo D, Martínez G, Rosado J, et al. The presence of rs9939609 of FTO and rs17782313 of MC4Rmay not be associated with obesity, elevated glucose or altered lipidprofile in school children of Queretaro: preliminary analysis. FASEB J. 2014;28:LB336. and Xi et al. 2626 Xi B, Shen Y, Zhang M, Liu X, Zhao X, Wu L, et al. The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China. BMC Med Genet. 2010;11:107. Regarding the AT gene, the GF was higher than that observed in the other studies shown in Table 4. The AA gene showed lower frequency when compared with the studies by Pereira et al. 44 Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016;92:521-7. and Reuter et al., 2424 Reuter CP, Burgos MS, Bernhard JC, Tornquist D, Klinger EI, Borges TS, et al. Association between overweight andobesity in schoolchildren with rs9939609 polymorphism (FTO) and family history for obesity. J Pediatr. 2016;92:493-8. but was higher than that of the studies by Flores et al. 2525 Flores K, Garcia O, Caamaño MC, Ronquillo D, Martínez G, Rosado J, et al. The presence of rs9939609 of FTO and rs17782313 of MC4Rmay not be associated with obesity, elevated glucose or altered lipidprofile in school children of Queretaro: preliminary analysis. FASEB J. 2014;28:LB336. and Xi et al. 2626 Xi B, Shen Y, Zhang M, Liu X, Zhao X, Wu L, et al. The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China. BMC Med Genet. 2010;11:107. In relation to the AF of T, a higher frequency was found than that of Pereira et al. 44 Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016;92:521-7. and Reuter et al., 2424 Reuter CP, Burgos MS, Bernhard JC, Tornquist D, Klinger EI, Borges TS, et al. Association between overweight andobesity in schoolchildren with rs9939609 polymorphism (FTO) and family history for obesity. J Pediatr. 2016;92:493-8. and a lower AF for the A allele.

Table 4
Prevalence of obesity and the allelic and genomic frequencies of different studies.

Discussion

The rs9939609 SNP of the FTO gene has been extensively studied in the scientific environment, especially in relation to its influence on the body. Wahlén et al., 2727 Wahlén K, Sjolin E, Hoffsted J. The common rs9939609 gene variant of the fat mass and obesity-associated gene FTO is related to fat cell lipolysis. J Lipid Res. 2008;49:607-11. studying the association between fat cell metabolism and this SNP, concluded that individuals who are heterozygous (AT) for this polymorphism would have a greater capacity for lipid deterioration due to a high concentration of an organic compound called glycerol. Another relevant finding about this SNP is its possible association with eating habits. It is believed that carriers of the A allele, both in homozygous and heterozygous states, would have a higher preference for fatty foods and little control to avoid their consumption.

In this study, the analyzed SNP was not associated with obesity. Moreover, it is important to emphasize that BMI values were close in relation to the different genotypes (AA, AT, and TT), which may highlight the absence of an association between this genotype and BMI.

The association of this polymorphism with obesity shows quite diverse conclusions in the literature and the frequency is quite varied, according to the assessed ethnic group or even whether the studies are carried out in adult populations, adolescents, or children.

In the study by Pereira et al., 44 Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016;92:521-7. aiming to evaluate the association between the FTO, AKT1, and AKTIP gene polymorphisms and childhood obesity, a sample of Brazilian children was studied, consisting of 195 obese and 153 non-obese individuals, but no association was found between the polymorphisms and obesity/overweight. According to the authors, although several variations of the FTO gene have been associated with obesity in populations with a European origin, their effects on other ethnicities remain to be established, and the Brazilian ethnic mixing may be a reason for the lack of association between this polymorphism and obesity.

Also in Brazil, another study pointed to the absence of association between metabolic and anthropometric parameters and FTO gene polymorphisms in a sample consisting of children and adolescents. The authors' explanation for this result is associated to the fact that the Brazilian population is mixed and heterogeneous. 1313 Souza NS, Melo ME, Fujiwara CT, Reinhardt HL, Santos A, Cercato C, et al. rs9939609 in the FTO gene is not related to obesity and worst metabolic profile in a cohort of obese Brazilian children and adolescents. Obesity. 2011;19:S1-234.

However, there are other studies, such as that of Reuter et al., 2424 Reuter CP, Burgos MS, Bernhard JC, Tornquist D, Klinger EI, Borges TS, et al. Association between overweight andobesity in schoolchildren with rs9939609 polymorphism (FTO) and family history for obesity. J Pediatr. 2016;92:493-8. which found a significant association between the A allele of the rS9939609 SNP of the FTO gene and obese and/or overweight individuals classified using the BMI as the main parameter. Liu et al. 2828 Liu G, Zhu H, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, et al. FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Med Genet. 2010;11:57. found that, irrespective of the sample's place of origin, in this case 289 young European and African-Americans aged 6-19 years, the presence of at least one A allele was directly related to the development of obesity.

Corroborating the present findings, the study by Flores et al., 2525 Flores K, Garcia O, Caamaño MC, Ronquillo D, Martínez G, Rosado J, et al. The presence of rs9939609 of FTO and rs17782313 of MC4Rmay not be associated with obesity, elevated glucose or altered lipidprofile in school children of Queretaro: preliminary analysis. FASEB J. 2014;28:LB336. conducted in Mexico, showed that in addition to the lack of a significant association between genotype and body composition in schoolchildren, both the allelic frequency of A and the genotypic frequency of AA were lower compared to the others, at 13% and 1%, respectively. However, the method used by these researchers for the evaluation of body composition was the absorptiometry technique using DXA.

The use of BMI to evaluate body composition is very common in the literature. In this study, the ADP technique was used to classify obesity, which is considered the gold standard method. It should be noted that this technique shows higher sensitivity and is more robust, classifying a greater number of individuals as obese when compared to BMI. 2929 Santos SK, Costa RM, Santos RA, Nunes KG, Santos JO, Cavalcanti V. Validação preliminar de equações antropométricas para a estimativa da gordura corporal em triatletas amadores. EFDeportes.com. 2015;:20. Available from: https://www.efdeportes.com/efd206/equacoes-antropometricas-em-triatletas-amadores.htm [cited 03.07.19].
https://www.efdeportes.com/efd206/equaco...

Body composition varies greatly in adolescents and depends on age, gender, ethnicity, height, and sexual maturation. 3030 Vieira AC, Alvarez MM, Marins VM, Sichieri R, Veiga GV. Desempenho de pontos de corte do índice de massa corporal de diferentes referências na predição de gordura corporal em adolescentes. Cad Saude Publica. 2006;22:1681-90. As shown in Table 4, different prevalence rates of obesity in adolescents can be found in the literature. Thus, the differences in the literature regarding the association between the FTO gene and obesity can be explained by the different methods used to classify obesity in adolescents.

The results of this study also indicate that the adolescents showed similar anthropometric measures (BMI, WC, WHtR, %BF), regardless of the genotype. Xi et al. 2626 Xi B, Shen Y, Zhang M, Liu X, Zhao X, Wu L, et al. The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China. BMC Med Genet. 2010;11:107. carried out a study with obese and non-obese children and adolescents from Beijing, China, in order to investigate the association between the FTO gene polymorphism (rs9939609) with WHtR, WC, %BF, BMI, systolic and diastolic blood pressure, and fasting glycemia, among other associated variables, and found a strong association of the anthropometric measurements with the polymorphism.

In this context, it can be observed how different the findings can be regarding this subject, which leads to different interpretations. One of them refers to the different prevalence rates of the alleles in relation to each population.

The allelic frequencies of the present study were very similar, since in the non-obese group they were 37.43% and 62.57%, whereas in the obese group they were 36.84% and 63.16% for the A and T alleles, respectively. For the whole sample, the frequencies were 37.23% for the A allele and 62.76% for the T allele. This indicates the absence of a possible association between the allelic frequencies and the group to which they belong, categorized by the percentage of body fat.

This is the first study to report data on the prevalence of alleles of this SNP in the population of the Brazilian Northeast, as there are no defined values that represent Brazil, so that a comparison can be made with populations from other countries or continents.

Therefore, the literature indicates that the association of this SNP with obesity can have quite varied results, and also when compared with different anthropometric parameters for obesity classification or body mass increase indicators. Gupta et al. 3131 Gupta V, Vinay DG, Rafiq S, Kranthikumar MV, Janipalli CS, Giambartolomei C, et al. Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs. Diabetologia. 2012;55:349-57. report that the ethnic composition of a population can have a strong influence on the allelic and genotypic frequencies of polymorphisms, leading to the need for studies that use similar methodologies in different populations, aiming to validate the results with robust and reproducible data.

In this sense, as a strong point, this is the first study carried out with adolescents from the Brazilian Northeast, using different anthropometric measures, such as the use of the ADP technique to classify the groups regarding obesity and, therefore, evaluate the association of the rs9939609 polymorphism of the FTO gene with obesity. The high cost to perform the study constitutes a weak point.

The analysis of the study data showed there was no association of the rs9939609 polymorphism of the FTO gene with the development of obesity, nor there was any difference between the means of BMI, WC, %BF, and WHtR with the different genotypes.

Thus, it is suggested that new studies using the same protocol should be performed, since there are controversies in the literature regarding the frequency of this SNP in relation to the studied ethnic group, as well as the discrepancy of the findings in relation to the age group of the analyzed populations.

  • Please cite this article as: Rodrigues LS, Santos AM, Lima MI, Simões VM, Pereira SR. Association between the FTO gene polymorphism and obesity in Brazilian adolescents from the Northeast region. J Pediatr (Rio J). 2020;96:630-7.
  • ☆☆
    Study conducted at Universidade Federal do Maranhão, São Luís, MA, Brazil.
  • Funding
    Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq and Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão - FAPEMA.

Acknowledgements

The authors are grateful to CNPq, FAPEMA, Hospital Universitário da UFMA, to the Genetics and Molecular Biology Laboratory of UFMA, to the coordination of the RPS Cohort Consortium of São Luís, and to all adolescents who agreed to participate in the study.

References

  • 1
    Ribeiro CM [Dissertação] Investigação da atividade do fluoreno, naftaleno, nonilfenol e procimidona sobre a adipogênese em cultura de células. Brasília: Universidade de Brasília; 2015.
  • 2
    Teixeira F, Mascarenhas LP, Suzuki CS, Smouter L, Novello D. Prevalência de fatores antropométricos e bioquímicos sobre o estado nutricional de adolescentes. RBONE. 2018;12:S1067-77.
  • 3
    Chae SM, Yeo JY, Hwang JH, Lee JH, Lim J, Kwon I. Weight control in adolescents: focus groups with Korean adolescents and their teachers. J Pediatr Nurs. 2017;33:4-9.
  • 4
    Pereira PA, Alvim-Soares AM, Sandrim VC, Lanna CM, Souza-Costa DC, Belo VA, et al. Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J). 2016;92:521-7.
  • 5
    Afman L, Müller M. Nutrigenomics: from molecular nutrition to prevention of disease. J Acad Nutr Diet. 2006;106:569-76.
  • 6
    Reilly JJ. Childhood obesity: an overview. Child Soc. 2007;21:390-6.
  • 7
    Instituto Brasileiro de Geografia e Estatística. Pesquisa de Orçamentos Familiares 2008-2009: antropometria e estado nutricional de crianças, adolescentes e adultos no Brasil. IBGE, Rio de Janeiro. 2010. Available from: https://biblioteca.ibge.gov.br/visualizacao/livros/liv45419.pdf [cited 28.01.19].
    » https://biblioteca.ibge.gov.br/visualizacao/livros/liv45419.pdf
  • 8
    Jesus ÍC, Alle LF, Percegona CG, Purim KS, Leite N. Relação entre polimorfismos genéticos, lipólise, metabolismo de lipídeos e exercícios aeróbios. Pensar a Prática. 2016;19. Available from: https://www.revistas.ufg.br/fef/article/view/37232 [cited 2.07.19].
    » https://www.revistas.ufg.br/fef/article/view/37232
  • 9
    Phani NM, Vohra M, Rajesh S, Adhikari P, Nagri SK, D'Souza SC, et al. Implications of critical PPARγ2, ADIPOQ and FTO gene polymorphisms in type 2 diabetes and obesity-mediated susceptibility to type 2 diabetes in an Indian population. Mol Genet Genomics. 2016;291:193-204.
  • 10
    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889-94.
  • 11
    Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP, et al. Association of the FTO gene with BMI. Obesity (Silver Spring). 2008;16:902-4.
  • 12
    Silva CF, Zandoná MR, Vitolo MR, Campagnolo PD, Rotta LN, Almeida S, et al. Association between a frequent variant of the FTO gene and anthropometric phenotypes in Brazilian children. BMC Med Genet. 2013;14:34.
  • 13
    Souza NS, Melo ME, Fujiwara CT, Reinhardt HL, Santos A, Cercato C, et al. rs9939609 in the FTO gene is not related to obesity and worst metabolic profile in a cohort of obese Brazilian children and adolescents. Obesity. 2011;19:S1-234.
  • 14
    Ramos CF, Magna LA, Mello MP, Silva R, Moura-Neto RS. Genetic variation and relationships at six VNTR loci in two distinct sample populations in Brazil. Ann Hum Biol. 2004;31:660-8.
  • 15
    Amorim P. Mini International Neuropsychiatric Interview (MINI): validação de entrevista breve para diagnóstico de transtornos mentais. Rev Bras Psiquiatr. 2000;22:106-15.
  • 16
    Sallis JF, Strikmiller PK, Harsha DW, Feldman HA, Ehlinger S, Stone EJ, et al. Validation of interviewer- and self-administered physical activity checklists for fifth grade students. Med Sci Sports Exerc. 1996;28:840-51.
  • 17
    Benedetti TR, Antunes PD, Rodriguez-Añez CR, Mazo GZ, Petroski EL. Reprodutibilidade e validade do Questionário Internacional de Atividade Física (IPAQ) em homens idosos. Rev Bras Med Esporte. 2007;13:11-6.
  • 18
    Ashwell M, Hsieh SD. Six reasons why the waist-to-height ratio is a rapid and effective global indicator for health risks of obesity and how its use could simplify the international public health message on obesity. Int J Food Sci Nutr. 2005;56:303-7.
  • 19
    WHO, World Health Organization. Growth reference 5-19 years; 2007. Available from: http://www.who.int/growthref/who2007_bmi_for_age/en/ [accessed 04.01.18].
    » http://www.who.int/growthref/who2007_bmi_for_age/en/
  • 20
    WHO, World Health Organization. BMI classification. 2006. Available from: http://apps.who.int/bmi/index.jsp?introPage=intro_3.html [accessed 03.03.18]
    » http://apps.who.int/bmi/index.jsp?introPage=intro_3.html
  • 21
    Siri WE. Body composition from fluid spaces and density: analysis of methods. Tech Meas Body Compos. 1961;61:223-44.
  • 22
    Williams DP, Going SB, Lohman TG, Harsha DW, Snnivasan SR, Webber LS, et al. Body fatness and risk for elevated blood pressure, total cholesterol, and serum lipoprotein ratios in children and adolescents. Am J Public Health. 1992;:82.
  • 23
    Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505-14.
  • 24
    Reuter CP, Burgos MS, Bernhard JC, Tornquist D, Klinger EI, Borges TS, et al. Association between overweight andobesity in schoolchildren with rs9939609 polymorphism (FTO) and family history for obesity. J Pediatr. 2016;92:493-8.
  • 25
    Flores K, Garcia O, Caamaño MC, Ronquillo D, Martínez G, Rosado J, et al. The presence of rs9939609 of FTO and rs17782313 of MC4Rmay not be associated with obesity, elevated glucose or altered lipidprofile in school children of Queretaro: preliminary analysis. FASEB J. 2014;28:LB336.
  • 26
    Xi B, Shen Y, Zhang M, Liu X, Zhao X, Wu L, et al. The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China. BMC Med Genet. 2010;11:107.
  • 27
    Wahlén K, Sjolin E, Hoffsted J. The common rs9939609 gene variant of the fat mass and obesity-associated gene FTO is related to fat cell lipolysis. J Lipid Res. 2008;49:607-11.
  • 28
    Liu G, Zhu H, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, et al. FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Med Genet. 2010;11:57.
  • 29
    Santos SK, Costa RM, Santos RA, Nunes KG, Santos JO, Cavalcanti V. Validação preliminar de equações antropométricas para a estimativa da gordura corporal em triatletas amadores. EFDeportes.com. 2015;:20. Available from: https://www.efdeportes.com/efd206/equacoes-antropometricas-em-triatletas-amadores.htm [cited 03.07.19].
    » https://www.efdeportes.com/efd206/equacoes-antropometricas-em-triatletas-amadores.htm
  • 30
    Vieira AC, Alvarez MM, Marins VM, Sichieri R, Veiga GV. Desempenho de pontos de corte do índice de massa corporal de diferentes referências na predição de gordura corporal em adolescentes. Cad Saude Publica. 2006;22:1681-90.
  • 31
    Gupta V, Vinay DG, Rafiq S, Kranthikumar MV, Janipalli CS, Giambartolomei C, et al. Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs. Diabetologia. 2012;55:349-57.

Publication Dates

  • Publication in this collection
    11 Nov 2020
  • Date of issue
    Sep-Oct 2020

History

  • Received
    24 Feb 2019
  • Accepted
    13 May 2019
  • Published
    30 July 2019
Sociedade Brasileira de Pediatria Av. Carlos Gomes, 328 cj. 304, 90480-000 Porto Alegre RS Brazil, Tel.: +55 51 3328-9520 - Porto Alegre - RS - Brazil
E-mail: jped@jped.com.br