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The contribution of FTO and UCP-1 SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals.

ABSTRACT: Obesity has become a common human disorder associated with significant morbidity and mortality and adverse effects on quality of life. Sequence variants in two candidate genes, FTO and UCP-1, have been reported to be overrepresented in obese Caucasian population. The association of these genes polymorphisms with the obesity phenotype in a multiethnic group such as the Brazilian population has not been previously reported.To assess the putative contribution of both FTO and UCP-1 to body mass index (BMI) and cardiovascular risk we genotyped SNPs rs9939609 (FTO) and rs6536991, rs22705565 and rs12502572 (UCP-1) from 126 morbidly obese subjects (BMI 42.9 ± 5.6 kg/m2, mean ± SE) and 113 normal-weight ethnically matched controls (BMI 22.6 ± 3.5 kg/m2, mean ± SE). Waist circumference, blood pressure, glucose and serum lipids were also measured. Each sample was also genotyped for 40 biallelic short insertion/deletion polymorphism (indels) for ethnic assignment and to estimate the proportion of European, African and Amerindian biogeographical ancestry in the Brazilian population.Cases did not differ from controls in the proportions of genomic ancestry. The FTO SNP rs9939609 and UCP-1 SNP rs6536991 were significantly associated with BMI (p= 0.04 and p<0.0001 respectively). An allele dose dependent tendency was observed for BMI for rs6536991 sample of controls. No other significant associations between any SNP and hypertension, hyperlipidemia and diabetes were noted after correction for BMI and no significant synergistic effect between FTO and UCP-1 SNPs with obesity were noted. There was not an association between rs9939609 (FTO) and rs6536991 (UCP-1) in with maximum weight loss after 1 year in 94 obese patients who underwent bariatric surgery.Our data are consistent with FTO rs9939609 and UCP-1 rs6536991 common variants as contributors to obesity in the Brazilian population.

SUBMITTER: Ramos AV

PROVIDER: S-EPMC3526455 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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The contribution of FTO and UCP-1 SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals.

Ramos Adauto V AV Bastos-Rodrigues Luciana L Resende Bruna A BA Friedman Eitan E Campanha-Versiani Luciana L Miranda Debora M DM Sarquis Marta M De Marco Luiz L

BMC medical genetics 20121107

<h4>Background</h4>Obesity has become a common human disorder associated with significant morbidity and mortality and adverse effects on quality of life. Sequence variants in two candidate genes, FTO and UCP-1, have been reported to be overrepresented in obese Caucasian population. The association of these genes polymorphisms with the obesity phenotype in a multiethnic group such as the Brazilian population has not been previously reported.<h4>Methods</h4>To assess the putative contribution of b ...[more]

PMID: 23134754

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Project description:BackgroundThe role of inflammatory states in cardiometabolic risks among patients with type 2 diabetes mellitus (T2DM) with similar degrees of obesity is unknown. The study aimed to compare cardiometabolic risk factors in inflammatory obesity phenotypes with regard to the role of the FTO rs9939609 gene polymorphism.Materials and methodsThis study was performed on 155 patients with T2DM (77 men and 78 women) in Ahvaz, Iran. Participants were grouped into four groups based on the presence of obesity and inflammation (high-sensitivity C-reactive protein ≥3.9 mg/L): low inflammatory normal weight (LINW), high inflammatory normal weight (HINW), low inflammatory obese (LIO), and high inflammatory obese (HIO). The genotypes of FTO rs9939609, including homozygous carriers of the FTO risk allele (AA), heterozygous carriers (AT), and carrying no risk allele (TT), were studied. The cardiometabolic risk factors, including anthropometric status, hypertension, lipid and glycemic profile, and inflammatory markers, were evaluated. The waist-hip ratio (WHR), mean arterial pressure (MAP), and atherogenic index of plasma (AIP) were calculated.ResultsThe patients in inflammatory groups (HINW and HIO) have significantly higher levels in AIP when compared to inflammatory healthy groups (LINW and LIO). No significant differences between any of the four group means were detected in WHR, blood pressure, MAP, glycemic status (fasting blood sugar and insulin), homeostatic model assessment, lipid profile (triglyceride, very low-density lipoprotein, high-density lipoprotein, low-density lipoprotein, and cholesterol), interleukin-6, and total antioxidant capacity. The most frequent of high-risk genotype (AA) of FTO rs9939609 was in HIO, LIO, HINW, and LINW.ConclusionT2DM patients with inflammatory condition have similar degree of increased atherogenic risk irrespective of obesity. The obesity-risk genotype AA of FTO gene was associated with an increased risk for inflammatory obesity in T2DM patients.

Project description:Intrauterine and postnatal overnutrition program hyperphagia, adiposity and glucose intolerance in offspring. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO.Female Sprague Dawley rats were exposed to chow or high fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1 (PND1), some litters were adjusted to 3 pups (vs. 12 control) to induce postnatal overnutrition. At PND20, rats were weaned onto chow or HFD for 15 weeks. FTO mRNA expression in the hypothalamus and liver, as well as hepatic markers of lipid metabolism were measured.At weaning, hypothalamic FTO mRNA expression was increased significantly in offspring of obese mothers and FTO was correlated with both visceral and epididymal fat mass (P<0.05); body weight approached significance (P?=?0.07). Hepatic FTO and Fatty Acid Synthase mRNA expression were decreased by maternal obesity. At 18 weeks, FTO mRNA expression did not differ between groups; however body weight was significantly correlated with hypothalamic FTO. Postnatal HFD feeding significantly reduced hepatic Carnitine Palmitoyltransferase-1a but did not affect the expression of other hepatic markers investigated. FTO was not affected by chronic HFD feeding.Maternal obesity significantly impacted FTO expression in both hypothalamus and liver at weaning. Early overexpression of hypothalamic FTO correlated with increased adiposity and later food intake of siblings exposed to HFD suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data. No effect of maternal obesity was observed on FTO in adulthood.

Project description:BackgroundObesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.Methodology/principal findingsa) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency > or =10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13 x 10(-7), corrected p = 0.0494; odds ratio (OR)(CT) 1.67, 95% confidence interval (CI) 1.22-2.27; OR(TT) 2.76, 95% CI 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.Conclusions/significanceOur GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.

Dataset Information

The contribution of FTO and UCP-1 SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals.

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The contribution of FTO and UCP-1 SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals.

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