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Gender-specific association of the rs6499640 polymorphism in the FTO gene with plasma lipid levels in Chinese children

Abstract

The fat mass- and obesity-associated gene (FTO) is significantly associated with obesity, but the associations of FTO with obesity-related traits are not fully described. We aimed to investigate the association of the FTO single nucleotide polymorphism (SNP) rs6499640 with lipid levels in Chinese children. A total of 3503 children aged 6-18 years were included in the present study. Lipid levels were analyzed and the SNP rs6499640 was genotyped using the TaqMan Allelic Discrimination Assay. Statistically significant associations were found between rs6499640 and low-density lipoprotein cholesterol (LDL-C) (p = 0.008), total cholesterol (TC) (p = 0.005), and triglycerides (TG) (p < 0.001) in girls under a dominant model adjusted for age and BMI. No statistical significance was found between the SNP and lipid levels in boys. We demonstrated for the first time that the SNP rs6499640 in FTO is associated with LDL-C, TC, and TG in Chinese girls. Our study identified a new risk locus for lipid levels in children.

Keywords:
children; FTO; lipid levels

Introduction

In recent years, the prevalence of dyslipidemia and obesity in children and adolescents has increased dramatically and these two diseases have been major challenges to public health (Keith et al., 2006Keith SW, Redden DT, Katzmarzyk PT, Boggiano MM, Hanlon EC, Benca RM, Ruden D, Pietrobelli A, Barger JL, Fontaine KR, et al. (2006) Putative contributors to the secular increase in obesity: Exploring the roads less traveled. Int J Obes 30:1585-1594.; Miller et al., 2011Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, et al. (2011) Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123:2292-2333.; Stone et al., 2014Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, et al. (2014) 2013 ACC / AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology / American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63:2889-2934.; Jacobson et al., 2015Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, et al. (2015) National lipid association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol 9:129-169.). Childhood high lipid levels and obesity strongly predispose to adult cardiovascular disease (CVD) and obesity (Tounian et al., 2001Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP and Bonnet D (2001) Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 358:1400-1404.; Simmonds et al., 2015Simmonds M, Burch J, Llewellyn A, Griffiths C, Yang H, Owen C, Duffy S and Woolacott N (2015) The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis. Health Technol Assess 19:1-336.).

Lipid levels and obesity are complex conditions influenced by genetic and environmental factors (Kathiresan et al., 2008Kathiresan S, Musunuru K and Orho-Melander M (2008) Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipidol 2:122-127.). Family and twin studies have indicated that more than 50% of changes in lipid levels is ascribed to genetic factors (Kort et al., 2000Kort EN, Ballinger DG, Ding W, Hunt SC, Bowen BR, Abkevich V, Bulka K, Campbell B, Capener C, Gutin A, et al. (2000) Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 66:1845-1856.). The fat mass- and obesity-associated gene (FTO) was the first gene associated to obesity in genome-wide association studies (GWAS) (Loos and Bouchard, 2008Loos R and Bouchard C (2008) FTO: The first gene contributing to common forms of human obesity. Obes Rev 9:246-250.). Thereafter, many of the single nucleotide polymorphisms (SNPs) of FTO have been confirmed to be associated with lipid levels (Scuteri et al., 2007Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, et al. (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3:e115.; Wang et al., 2012Wang J, Mei H, Chen W, Jiang Y, Sun W, Li F, Fu Q and Jiang F (2012) Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty. Int J Obes 4:542-547.). Our previous study suggested that the FTO SNP rs6499640 was associated with obesity in Chinese children (Wu L et al., 2010Wu L, Xi B, Zhang M, Shen Y, Zhao X, Cheng H, Hou D, Sun D, Ott J, Wang X, et al. (2010) Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. Diabetes 59:3085-3089.). However, the associations of this SNP with lipid levels are not described.

As obesity is closely related to high lipid levels, it is possible that both diseases share a common genetic background. Evidence from several studies indicates that the association between FTO variants and lipid levels may be BMI-dependent and may differ by gender (Kring et al., 2008Kring SI, Holst C, Zimmermann E, Jess T, Berentzen T, Toubro S, Hansen T, Astrup A, Pedersen O and Sørensen TI (2008) FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS One 3:e2958.; Fang et al., 2010Fang H, Li Y, Du S, Hu X, Zhang Q, Liu A and Ma G (2010) Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. BMC Med Genet 11:136.; Elouej et al., 2016Elouej S, Belfki-Benali H, Nagara M, Lasram K, Attaoua R, Sallem OK, Kamoun I, Chargui M, Romdhane L, Jamoussi H, et al. (2016) Association of rs9939609 polymorphism with metabolic parameters and FTO risk haplotype among Tunisian metabolic syndrome. Metab Syndr Relat 14:121-128.), but different results have been found in other studies (Muñoz-Yáñez et al., 2016Muñoz-Yáñez C, Pérez-Morales R, Moreno-Macías H, Calleros-Rincón E, Ballesteros G, González RA and Espinosa J (2016) Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children. Genet Mol Biol 39:547-553.; Qureshi et al., 2017Qureshi SA, Mumtaz A, Shahid SU and Shabana NA (2017) Rs3751812, a common variant in fat mass and obesity-associated (FTO) gene, is associated with serum high- and low-density lipoprotein cholesterol in Pakistani individuals. Nutrition 39-40:92-95.).

In the present study, we evaluated the associations between FTO rs6499640 and lipid levels and examined gender-specific associations in Chinese children.

Materials and Methods

Subjects

Subjects were recruited from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study (Mi et al., 2006Mi J, Cheng H, Hou DQ, Duan JL, Teng HH and Wang YF (2006) Prevalence of overweight and obesity among children and adolescents in Beijing in 2004. Chin J Epidemiol 27:474-479.), which was a cross-sectional population-based study that included a questionnaire, medical examination, anthropometric measurement and finger capillary blood test in a representative sample of Beijing school-age children (n=19,593, aged 6-18 years, 50% boys) in 2004. From the BCAMS study, a subgroup of 1229 obese children and 2274 non-obese children were selected. The BCAMS study was approved by the Ethics Committee at the Capital Institute of Pediatrics in Beijing. Written informed consent was signed by participants’ parents or guardians.

Anthropometric measurements and biochemical analyses

Height and weight were measured according to our standard protocol (Mi et al., 2006Mi J, Cheng H, Hou DQ, Duan JL, Teng HH and Wang YF (2006) Prevalence of overweight and obesity among children and adolescents in Beijing in 2004. Chin J Epidemiol 27:474-479.). The lipid levels were assessed by enzymatic methods for total cholesterol (TC) and triglyceride (TG), and clearance methods for high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), using the Hitachi 7060C Automatic Biochemistry Analysis System.

Definition of obesity and dyslipidemia

Obesity was defined by using the Chinese age- and sex-specific body mass index (BMI) cutoffs (Supplementary Table S1), recommended by the Working Group on Obesity in China (Ji and Working Group on Obesity in China, 2005Ji CY and Working Group on Obesity in China (2005) Report on childhood obesity in China (1) - body mass index reference for screening overweight and obesity in Chinese school-age children. Biomed Environ Sci 18:390-400.). Dyslipidemia was diagnosed if the child fell in at least one of the following four categories: 1) high TC: TC ≥ 5.18 mmol/L; 2) high TG: TG ≥ 1.70 mmol/L; 3) high LDL-C: LDL-C ≥ 3.37 mmol/L; 4) low HDL-C: HDL-C ≤ 1.04 mmol/L (Editorial Board of Chinese Journal of Pediatrics et al., 2009Editorial Board of Chinese Journal of Pediatrics; Subspecialty Group of Child Health Care, The Society of Pediatrics, Chinese Medical Association; Subspecialty Group of Cardiovascular Disease, The Society of; Pediatrics, Chinese Medical Association; Subspecialty Group of Atherosclerosis, The Society of Cardiovascular and Disease, Chinese Medical Association (2009) Experts consensus for prevention and treatment of dyslipidemia in children and adolescents. Chin J Pediatr 47:426-428.).

Genotyping

Genomic DNA was isolated from peripheral white blood cells using the salt fractionation method. The SNP rs6499640 was genotyped using the TaqMan Allelic Discrimination Assay with the GeneAmp 7900 Sequence Detection System (Applied Biosystems, USA). Genotyping call rates for SNP was > 98%. In order to validate the accuracy of genotyping, we repeated 70 samples randomly for each SNP and observed 100% concordance between the results of the two tests.

Statistical analysis

Statistical analyses were performed using the statistical software SPSS, version 19.0 (IBM Corp, USA). Quantitative variables were presented as the mean ± standard deviation (SD) and categorical variables were presented as percentages. Hardy-Weinberg equilibrium was assessed using the chi-square test. The difference of lipid levels (LDL-C, TC, TG, and HDL-C) between AA and GG+GA groups was analyzed by covariance analysis. Adjusted odds ratios (ORs) for high LDL-C, high TC, high TG and low HDL-C were computed by logistic regression with genotype, age, gender, and BMI or obesity status as the independent variables. p < 0.05 was used to indicate statistically significant differences. False discovery rate (FDR) approach was used to correct for multiple testing. Power calculation was performed using Quanto softwareQuanto, Software, http://hydra.usc.edu/gxe/ (August 20, 2017)
http://hydra.usc.edu/gxe/...
( http://hydra.usc.edu/gxe/).

Results

Table 1 shows the demographic and clinical characteristics of the study population. We genotyped the SNP rs6499640 in FTO in the cohort, and the genotypes of the SNP (the number of GG, GA, and AA was 2401, 932 and 110, respectively) were in Hardy–Weinberg equilibrium (p = 0.095). Comparison of characteristics between boys and girls are shown in Table 1. Girls had higher TC, TG, and LDL-C values than boys (all p < 0.05).

Table 1
Characteristics of the study population.

The difference in LDL-C, TC, TG, and HDL-C with different genotypes of rs6499640 are shown in Table 2. There were significant differences in LDL-C (p = 0.002), TC (p = 0.001), and TG (0.019) with different genotypes (AA, GG+GA) after adjustment for age and gender. As SNP rs6499640 was significantly associated with BMI, we also adjusted for BMI or obesity status besides age and gender. The SNP rs6499640 was significantly different in LDL-C (p = 0.002), TC (p = 0.001), and TG (0.007) with different genotypes (AA, GG+GA) under the dominant model after adjusting for age, gender, and BMI. The associations of rs6499640 with high LDL-C, high TC, high TG, low HDL-C, and dyslipidemia were also tested, but no significance was found (Table S2).

Table 2
Difference in lipid levels with different genotypes of rs6499640.

Table 3 shows the differences in LDL-C, TC, TG, and HDL-C levels with different genotypes of rs6499640 under the dominant model by gender. After adjusting for age and BMI, we found significant differences in LDL-C (p = 0.008), TC (p = 0.005), and TG (p < 0.001) with different genotypes (AA, GG+GA) in girls. The above results were not found in boys, and there was no association between rs6499640 and high LDL-C, high TC, high TG, low HDL-C and dyslipidemia in boys and girls (Table S2).

Table 3
Difference in lipid levels with different genotypes of rs6499640 by gender.

Discussion

In this study, we examined the SNP rs6499640 in FTO in a Chinese children population. Our results indicated that the association of this SNP with lipid levels is independent of obesity. This supports the suggested activity of FTO protein, in conjunction with C/EBP, as a co-activator of PPAR gamma, which is involved in adipocyte functions, such as lipid metabolism and differentiation (Wu Q et al., 2010Wu Q, Saunders RA, Szkudlarek-Mikho M, Serna Ide L and Chin KV (2010) The obesity-associated FTO gene is a transcriptional coactivator. Biochem Biophys Res Commun 401:390-395.).

The association between FTO and lipid levels is difficult to clarify. Many factors can affect the authenticity of the association. The reason for the discrepant results among Chinese studies might be due to the different ages of the samples. We recruited children aged 6-18 years and surveyed the effects of rs6499640 on lipid levels. However, a study in Chinese adolescents (n = 842) aged from 14 to 18 years did not show associations between rs6499640 and TC and TG (Wu et al., 2014Wu J, Xu J, Zhang Z, Ren J, Li Y, Wang J, Cao Y, Rong F, Zhao R, Huang X, et al. (2014) Association of FTO polymorphisms with obesity and metabolic parameters in Han Chinese adolescents. PLoS One 9:e98984.). The interference of environmental effects on genetics factors is lower in young people than in older people and thus, young populations are the ideal group to study the effects of genetic factors on lipids metabolism. The non-significant association between rs6499640 and dyslipidemia in our study might be due to a lack of case samples. With time, there are accumulative risk effects on dyslipidemia, but we studied children and adolescents and found results consistent with several previous studies (Fang et al., 2010Fang H, Li Y, Du S, Hu X, Zhang Q, Liu A and Ma G (2010) Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. BMC Med Genet 11:136.; Muñoz-Yáñez et al., 2016Muñoz-Yáñez C, Pérez-Morales R, Moreno-Macías H, Calleros-Rincón E, Ballesteros G, González RA and Espinosa J (2016) Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children. Genet Mol Biol 39:547-553.).

This study also suggested sex-dependent effects of SNP rs6499640 on lipid levels. The association could be partly explained by the fact that boys and girls differ in fat mass percentage and adipocytokines. Our previous studies have found differences in leptin and adiponectin levels between male and female students, and these adipocytokines are related to insulin resistance, while fasting insulin and insulin sensitivity might play important roles in the achievement of critical lipid levels; (Sinaiko et al., 2001Sinaiko AR, Jacobs Jr DR, Steinberger J, Moran A, Luepker R, Rocchini AP and Prineas RJ (2001) Insulin resistance syndrome in childhood: Associations of the euglycemic insulin clamp and fasting insulin with fatness and other risk factors. J Pediatr 139:700-707.; Recasens et al., 2004Recasens M, Ricart W and Fernández-Real JM (2004) Obesity and inflammation. Rev Demed Univ Nav 48:49-54.; Mi et al., 2010Mi J, Munkonda MN, Li M, Zhang MX, Zhao XY, Fouejeu PC and Cianflone K (2010) Adiponectin and leptin metabolic biomarkers in chinese children and adolescents. J Obes 2010:892081.). Another reason might be the interaction between genes and environment in males and females. In this study, boys and girls were in different puberty stages (Table S3), which have large behavioral, physiological, and endocrine changes (Wang et al., 2012). Further investigations are needed to understand this mechanism in detail.

Several studies have described the associations between FTO and lipid levels. One study investigated the association between the FTO SNP rs9939609, PPARG2 SNP rs1801282, ADIPOQ SNPs rs4632532, and rs182052 with obesity-related traits in Mexican children with a high prevalence of obesity (43.7%) (Muñoz-Yáñez et al., 2016Muñoz-Yáñez C, Pérez-Morales R, Moreno-Macías H, Calleros-Rincón E, Ballesteros G, González RA and Espinosa J (2016) Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children. Genet Mol Biol 39:547-553.). They found that the variant A of SNP rs9939609 was associated with LDL-C after adjusting for age, gender, and BMI. Furthermore, Qureshi et al. (2017)Qureshi SA, Mumtaz A, Shahid SU and Shabana NA (2017) Rs3751812, a common variant in fat mass and obesity-associated (FTO) gene, is associated with serum high- and low-density lipoprotein cholesterol in Pakistani individuals. Nutrition 39-40:92-95. suggested that the rs3751812-T allele is a risk factor that may increase LDL-C and decrease HDL-C in a study of 475 Pakistani adults. Another study investigated the associations between SNP rs9939609 and metabolic parameters in boys and girls separately (Elouej et al., 2016Elouej S, Belfki-Benali H, Nagara M, Lasram K, Attaoua R, Sallem OK, Kamoun I, Chargui M, Romdhane L, Jamoussi H, et al. (2016) Association of rs9939609 polymorphism with metabolic parameters and FTO risk haplotype among Tunisian metabolic syndrome. Metab Syndr Relat 14:121-128.). They found that the FTO rs9939609 showed a significant association with TC among Tunisian women. When BMI was further adjusted, the association of this polymorphism with TC remained significant. Fang et al. (2010)Fang H, Li Y, Du S, Hu X, Zhang Q, Liu A and Ma G (2010) Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. BMC Med Genet 11:136. found that FTO rs9939609 was associated with log TG in Chinese children, and Kring et al. (2008)Kring SI, Holst C, Zimmermann E, Jess T, Berentzen T, Toubro S, Hansen T, Astrup A, Pedersen O and Sørensen TI (2008) FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS One 3:e2958. observed an association between FTO rs9939609 and low HDL-C, but the associations disappeared after adjusting for BMI. Many studies have adjusted the effects of FTO SNP on lipid levels for BMI, and most found positive results, as did this study. From the studies that analyzed this association, we can observe that the minor allele frequency (MAF) of the FTO SNPs included in those studies is higher than that of the respective populations (Table S4). That may be one of the reasons those articles have positive results; the MAF of different FTO variants showed that this gene may play an important part in the common forms of lipid levels. We also investigated the linkage disequilibrium about the FTO SNPs in CHB populations (https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/, https://www.broadinstitute.org/haploview/haploview; the results (rs6499640 vs rs3751812: D’=1, r2=0.001, rs6499640 vs rs9939609: D’=1, r2=0.004) provided direct evidence that the rs6499640 SNP influences lipid levels.

Our study shows that the associations of FTO with lipid levels remained significant after further adjustment for BMI, suggesting that the effects of FTO on obesity and lipid levels are independent of each other, but we didn’t find the associations of interactions between FTO and obesity status with lipid levels (Table S5). Further study is needed to clarify whether obesity changes the lipid profile due to disturbed metabolism or the abnormal lipid profile leads to obesity.

In conclusion, we demonstrated for the first time that the SNP rs6499640 in FTO is associated with TC, LDL-C, and TG in Chinese girls. No significant associations were found in boys. These novel findings identify a new risk locus associated with lipid levels in children. The function of FTO remains to be further studied to help elucidate the pathogenic role of FTO in lipid levels.

Acknowledgments

This study was financially supported by the National Basic Research Program of China (973 Program, grant number 2013CB530605) and the National Natural Science Foundation of China (grant number 81473062).

References

  • Editorial Board of Chinese Journal of Pediatrics; Subspecialty Group of Child Health Care, The Society of Pediatrics, Chinese Medical Association; Subspecialty Group of Cardiovascular Disease, The Society of; Pediatrics, Chinese Medical Association; Subspecialty Group of Atherosclerosis, The Society of Cardiovascular and Disease, Chinese Medical Association (2009) Experts consensus for prevention and treatment of dyslipidemia in children and adolescents. Chin J Pediatr 47:426-428.
  • Elouej S, Belfki-Benali H, Nagara M, Lasram K, Attaoua R, Sallem OK, Kamoun I, Chargui M, Romdhane L, Jamoussi H, et al. (2016) Association of rs9939609 polymorphism with metabolic parameters and FTO risk haplotype among Tunisian metabolic syndrome. Metab Syndr Relat 14:121-128.
  • Fang H, Li Y, Du S, Hu X, Zhang Q, Liu A and Ma G (2010) Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. BMC Med Genet 11:136.
  • Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, et al. (2015) National lipid association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol 9:129-169.
  • Ji CY and Working Group on Obesity in China (2005) Report on childhood obesity in China (1) - body mass index reference for screening overweight and obesity in Chinese school-age children. Biomed Environ Sci 18:390-400.
  • Kathiresan S, Musunuru K and Orho-Melander M (2008) Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipidol 2:122-127.
  • Keith SW, Redden DT, Katzmarzyk PT, Boggiano MM, Hanlon EC, Benca RM, Ruden D, Pietrobelli A, Barger JL, Fontaine KR, et al. (2006) Putative contributors to the secular increase in obesity: Exploring the roads less traveled. Int J Obes 30:1585-1594.
  • Kort EN, Ballinger DG, Ding W, Hunt SC, Bowen BR, Abkevich V, Bulka K, Campbell B, Capener C, Gutin A, et al. (2000) Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23. Am J Hum Genet 66:1845-1856.
  • Kring SI, Holst C, Zimmermann E, Jess T, Berentzen T, Toubro S, Hansen T, Astrup A, Pedersen O and Sørensen TI (2008) FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS One 3:e2958.
  • Loos R and Bouchard C (2008) FTO: The first gene contributing to common forms of human obesity. Obes Rev 9:246-250.
  • Mi J, Cheng H, Hou DQ, Duan JL, Teng HH and Wang YF (2006) Prevalence of overweight and obesity among children and adolescents in Beijing in 2004. Chin J Epidemiol 27:474-479.
  • Mi J, Munkonda MN, Li M, Zhang MX, Zhao XY, Fouejeu PC and Cianflone K (2010) Adiponectin and leptin metabolic biomarkers in chinese children and adolescents. J Obes 2010:892081.
  • Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, et al. (2011) Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123:2292-2333.
  • Muñoz-Yáñez C, Pérez-Morales R, Moreno-Macías H, Calleros-Rincón E, Ballesteros G, González RA and Espinosa J (2016) Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children. Genet Mol Biol 39:547-553.
  • Qureshi SA, Mumtaz A, Shahid SU and Shabana NA (2017) Rs3751812, a common variant in fat mass and obesity-associated (FTO) gene, is associated with serum high- and low-density lipoprotein cholesterol in Pakistani individuals. Nutrition 39-40:92-95.
  • Recasens M, Ricart W and Fernández-Real JM (2004) Obesity and inflammation. Rev Demed Univ Nav 48:49-54.
  • Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, et al. (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3:e115.
  • Simmonds M, Burch J, Llewellyn A, Griffiths C, Yang H, Owen C, Duffy S and Woolacott N (2015) The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis. Health Technol Assess 19:1-336.
  • Sinaiko AR, Jacobs Jr DR, Steinberger J, Moran A, Luepker R, Rocchini AP and Prineas RJ (2001) Insulin resistance syndrome in childhood: Associations of the euglycemic insulin clamp and fasting insulin with fatness and other risk factors. J Pediatr 139:700-707.
  • Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, et al. (2014) 2013 ACC / AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology / American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63:2889-2934.
  • Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP and Bonnet D (2001) Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 358:1400-1404.
  • Wang J, Mei H, Chen W, Jiang Y, Sun W, Li F, Fu Q and Jiang F (2012) Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty. Int J Obes 4:542-547.
  • Wu J, Xu J, Zhang Z, Ren J, Li Y, Wang J, Cao Y, Rong F, Zhao R, Huang X, et al. (2014) Association of FTO polymorphisms with obesity and metabolic parameters in Han Chinese adolescents. PLoS One 9:e98984.
  • Wu L, Xi B, Zhang M, Shen Y, Zhao X, Cheng H, Hou D, Sun D, Ott J, Wang X, et al. (2010) Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. Diabetes 59:3085-3089.
  • Wu Q, Saunders RA, Szkudlarek-Mikho M, Serna Ide L and Chin KV (2010) The obesity-associated FTO gene is a transcriptional coactivator. Biochem Biophys Res Commun 401:390-395.

Internet Resources

  • Associate Editor: Maria Luiza Petzl-Erler

Publication Dates

  • Publication in this collection
    04 June 2018
  • Date of issue
    Apr./June 2018

History

  • Received
    19 Apr 2017
  • Accepted
    25 Oct 2017
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