Gene variants have been reported in association with obesity or obesity-related phenotypes. However, lack of replication has long been a big challenge in these genetic association studies . The association of the FTO gene with human obesity is robust in populations of European descendent [8–10]. To date, negative results have involved non-European populations [13, 14, 16–19]. Although the genetic architecture of the FTO locus has not been examined in great detail in these populations evidence is emerging that rs9939609 might be in tight linkage disequilibrium with a casual variant in populations of European descendent. However, this linkage disequilibrium may break down in other ethnic and racial groups suggesting that these population have differences arisen through evolutionary divergence, perhaps as a result of some negative selection pressure against the FTO risk alleles in some African and East Asian population [12–18].
Interestingly, the study by Frayling et al. (2007)  identified FTO through a genome-wide association study for type 2 diabetes. After adjusting for BMI, the association with type 2 diabetes was completely abolished, suggesting that the FTO-type 2 diabetes association was mediated through BMI. Subsequently, the association with BMI and obesity was unequivocally replicated in 13 cohorts comprising more the 38000 individuals . The effect of FTO SNPs on BMI is modest, with those individuals homozygous for the risk allele weighting, on average, 3 kg more than those homozygous for the protective allele . However, physical activity can attenuate this FTO association . BMI-associated SNPs lie within a 47 kilobase (kb) linkage disequilibrium (LD) block encompassing parts of the first two introns as well as exon 2 of the FTO gene. Thus, the association signal could be due to correlation between FTO intronic SNPs and variation elsewhere in the gene or control elements of other genes . The precise mechanism by which the FTO gene leads to obesity development is unclear . The FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase that is present in many tissues and is most abundant in the hypothalamus where the control center of energy balance lie [8, 31]. Studies in mice showing that Fto mRNA levels are regulated by feeding and fasting have provided a mechanistic link between FTO and body weight and energy homeostasis . Cecil et al. (2008)  demonstrated that a predisposition to obesity does not appear to be involved in the regulation of expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods.
In this report we confirmed the association of the FTO variant with BMI in a population of Brazilians with multi-ethnic ancestry. The obese population who was homozygous for the risk allele weighted 3.1kg and 1.3kg/m2 more than those homozygous for the protective allele as demonstrated by Frayling et al. (2007) . We did not find evidence of association with type 2 diabetes or most of the obesity–related phenotypes in quantitative trait analyses mainly after stratification for BMI as also demonstrated by Frayling et al. (2007) .
In addition, many studies have looked for many candidate genes to determine genetic factors implicated in the pathogenesis of obesity, related metabolic disorders and diabetes. UCP
1, which plays a major role in thermogenesis, was suggested to be one of these candidate genes . Uncoupling protein 1 (UCP1), a 32kDa protein located in the inner mitochondrial membrane, is abundant in brown adipose tissue (BAT), in which UCP-1 allows to re-enter the matrix, bypassing the ATP synthase. The usually low proton conductance of the membrane is increased, which results in an acceleration of mitochondrial respiration. The dissipation of the proton electrochemical gradient leads to an uncoupled respiration and heat production, the main function of BAT (34). UCP-1 expression is strongly induced when thermogenesis is required . UCP1 has been reported to play an important role in thermogenesis and energy expenditure and is implicated in the pathogenesis of obesity and metabolic disorders in human [35–37]. The influence of the polymorphism of UCP
1 gene on obesity had been reported in some studies [20, 21] while others found no association [38–40].
In our study we investigated the effect of UCP-1 gene SNPs on obesity and obesity related phenotypes among Brazilian people. Our findings show a significant association between the minor allele rs6536991 but not on rs2270565 and rs12502572 with obesity. Again, after BMI stratification, the correlation between rs6536991 and type 2 diabetes, hypertension and dislipidemia disappeared. Interestingly, the effect of the rs6536991 was greater than the effect of FTO rs9939609 in our population, with those individuals homozygous for the risk allele weighting were on average, 3kg/m2 of BMI more than those homozygous for the protective allele. Taken together we found evidence that rs9939609 in the FTO and rs6536991 in the UCP-1 gene increased the risk of obesity but not obesity related phenotypes in the Brazilian population studied. The SNPs rs2270565 and rs12502572 from the UCP-1 were not correlated with obesity and obesity related phenotype.
The reasons for the non effect of the SNPs rs2270565 and rs12502572 could be the relatively small sample size we report or because they were not in linkage disequilibrium compared to rs6536991, which showed association, justifying different behaviors between them. Indeed, a sample size of 445 and 350 people, respectively, would be required to ensure an 80% power. Furthermore, we did not find a significant synergistic effect between FTO and UCP
1 SNPs with BMI and no significant correlation with maximum weight loss one year of bariatric surgery. Further studies examining a larger sample size would be necessary to detect this synergistic effect or this association with weight loss one year after bariatric surgery .
Brazilians form a very heterogeneous population, which is the result of five centuries of inter-ethnic crosses between peoples from three continents: the European colonizers mainly represented by the Portuguese, African slaves, and the autochthonous Amerindians. Genomic controls help to rule out alternate explanations regarding the influence of racial and ethnic ancestry on this important health outcome . These three groups have admixed to a point which there is very little correlation between skin color and ancestry . Despite the more representative European ancestry, the differences in the proportions of genomics ancestry between the two groups were not significant. These findings bring interesting remarks on the social and genetic epidemiology of obesity.
Some potential limitations should be considered in our study. First, a limited sample size from a single center albeit representative of our population. Second, interaction between lifestyle, physical activity and genes could be a confounding factor and these were not investigated.
Despite the recent success in identifying obesity gene variants using the genome wide association approach, it is well established that such variants do not cause obesity without the individual being exposed to an obesity-promoting environment. Also, only a small fraction of the genetic contribution to obesity has presently been identified . This could be owing to a complex interplay between genetic and environmental factors masking the effect of specific genetic variants.