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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The timing of associations between common genetic variants for weight or body mass index (BMI) across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO (rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2-20 years) or adulthood (20-53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003-0.010, P < 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08-0.19), and then weakened during adulthood (-0.003 SDS/A-allele/year, -0.005 to -0.001, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; 0.001-0.008, P = 0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07-0.18), and weakened during adulthood (-0.002 SDS/C-allele/year, -0.004 to 0.000, P = 0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain.
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PMID:Life course variations in the associations between FTO and MC4R gene variants and body size. 1988 Aug 56

Fat mass and obesity associated gene ( FTO) is the most relevant polygene for obesity to date. It has been identified by genome wide association studies concerning body weight regulation. However, its functional relevance for the pathogenesis of obesity remains elusive. Studies in rodents provide data pointing to a central role of FTO through regulation of food intake. In addition, peripheral effects of FTO are also discussed in the literature. This review highlights the possible relevance of FTO for weight regulation and obesity development in central and peripheral tissues with a special focus on adipose tissue.
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PMID:FTO - Friend or foe? 1992 17

Obesity is a global and growing problem. The detrimental health consequences of obesity are significant and include co-morbidities such as diabetes, cancer and coronary heart disease. The marked rise in obesity observed over the last three decades suggests that behavioural and environmental factors underpin the chronic mismatch between energy intake and energy expenditure. However, not all individuals become obese, suggesting that there is considerable variation in responsiveness to 'obesogenic' environments. Some individuals defend easily against a propensity to accumulate fat mass and become overweight whilst others are predisposed to gain weight, possibly as a function of genotype. The genetic contribution to obesity is well established. Common obesity is polygenic, involving complex gene-gene and gene-environment interactions, and it is these interactions that produce the multi-factorial obese phenotypes. Candidate gene variants for polygenic obesity appear to disrupt pathways involved in the regulation of energy intake and expenditure and include adrenergic receptors, uncoupling proteins, PPARG, POMC, MC4R and a set of single nucleotide polymorphisms in the FTO locus. Notably, the FTO gene is the most robust gene for common obesity characterised to date, and recent data shows that the FTO locus seems to confer risk of obesity through increasing energy intake and reduced satiety. Gene variants involved in pathways regulating addiction and reward behaviours may also play a role in predisposition to obesity. Understanding the routes through which the genotype is expressed will ultimately provide opportunities for developing strategies to intervene, as the interaction between genotype and environment is potentially modifiable through behaviour change.
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PMID:Gene-environment interactions in obesity. 1995 87

Obesity has become an epidemic in many countries and is one of the major risk conditions for disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension. Recent genome-wide association studies have identified two genes (FTO and near MC4R) that were unequivocally associated with body mass index (BMI) and obesity. For the Genetic Analysis Workshop 16, data from the Framingham Heart Study were made available, including longitudinal anthropometric and metabolic traits for 7130 Caucasian individuals over three generations, each with follow-up data at up to four time points. We explored the associations between four single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633) with weight and BMI under an additive model. We applied multilevel linear mixed model for continuous outcomes, using the Affymetrix 500k genome-wide genotype data for the four SNPs. The results of the multilevel modeling in the entire sample indicated that the minor alleles of the four SNPs were associated with higher weight and higher BMI. The most significant associations were between rs9939609 and weight (p = 4.7 x 10-6) and BMI (p = 8.9 x 10-8). The results also showed that, for SNPs at FTO, the homozygotes for the minor allele had the most pronounced increase in weight and BMI, while the common allele homozygotes gained less weight and BMI during the follow-up period. Linkage disequilibrium (LD) between the two FTO SNPs was strong (D' = 0.997, r2 = 0.875) but their haplotype was not significantly associated with either weight or BMI. The two SNPs near MC4R were in weak LD (D' = 0.487, r2 = 0.166).
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PMID:A multilevel linear mixed model of the association between candidate genes and weight and body mass index using the Framingham longitudinal family data. 2001 80

The association of the FTO gene polymorphism, rs9939609, with obesity was examined using the population of the Takahata study (n (M/F): 2,639 (1,168 / 1,470); age: 63.0 +/- 10.2 years), a Japanese community-based study. The effects of lifestyle-related factors, including nutritional intake and physical activities, on the association were also examined. Body mass index (BMI) was significantly associated with the FTO gene polymorphism (p<0.001). A case-control association study of the FTO gene polymorphism with obesity using multiple logistic regression analysis showed a significant association of the genotype AA (odds ratio, 1.53 [95% confidential interval, 1.04-2.24]) after adjustment for age and gender. Analysis to examine the differences in lifestyle-related factors among the genotype groups showed a significant difference in the energy expenditure for moderate to high-intensity physical activity (PA) (> or = 3.0 METs) (p=0.012) with a significant decrease toward the genotype AA (p=0.027). The effect of energy expenditure for moderate to high-intensity PA on the association of the polymorphism with obesity was then examined using study groups stratified based on the energy expenditure for moderate to high-intensity PA (Low-PA and High-PA). The BMI was significantly higher in the genotype AA in the Low-PA group (p=0.016) but not in the High-PA group (p=0.103). Furthermore, the genotype AA was significantly associated with obesity (odds ratio, 2.39 [95% confidential interval, 1.19-4.80]) in the Low-PA group but not in the High- PA group (p=0.650). The FTO gene, rs9939609, was associated with obesity, and the association was evident in subjects with low-PA, suggesting a PA-dependent association.
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PMID:Association of the common fat mass and obesity associated (FTO) gene polymorphism with obesity in a Japanese population. 2005 47

The persistence of obesity from early childhood to late middle age is well known. We reviewed the results from existing genetic studies on tracking of BMI to discover how much genetic and environmental factors contribute to this tracking of obesity. In total, we found 5 genetic longitudinal studies on childhood obesity and 8 on obesity in adulthood. One was an adoption study, 3 were family studies, and 9 were twin studies. All were based on Caucasian populations, and one included genetic level information (the FTO gene). Strong genetic continuity in BMI was found from early childhood to onset of adulthood. Although new genetic factors started to affect BMI during the growth period, genetic correlations remained high. Evidence of the effect of common environment on the tracking of BMI during childhood was also found. The heritability estimates reported in twin studies ranged from 0.57 to 0.86 for the trend of BMI from early adulthood to late middle age. The three family studies gave lower estimates. Important unresolved questions are the genetics of BMI change in old age, the genetics of body composition change, the genetic architecture of tracking of obesity in ethnic groups other than Caucasians, and the interplay between genes and environment underlying the development and tracking of obesity.
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PMID:Genetics of tracking of body mass index from birth to late middle age: evidence from twin and family studies. 2005 25

Several common variants in the intron 1 of FTO (fat mass and associated obesity) gene have been reliably associated with BMI and obesity in European populations. We analyzed two variants (rs9939609 and rs8050136) in 4,189 Chinese Han individuals and conducted a meta-analysis of published studies in Asian population to investigate whether these variants are associated with type 2 diabetes (T2D) and obesity in Asian population. In this study, both the minor allele A of rs9939609 and the minor allele A of rs805136 were associated with increased risk of T2D, independent of measures of BMI; the odds ratios (ORs) per copy of the risk allele were 1.19 for rs9939609 (95% confidence interval (CI), 1.04-1.37; P = 0.01) and 1.22 for rs8050136 (95% CI, 1.07-1.40; P = 0.004) after adjusting for age, sex, and BMI. Our results also showed association with risk of obesity (rs9939609: OR = 1.39 (95% CI 1.04-1.85), P = 0.02; rs8050136: OR = 1.45 (95% CI 1.09-1.93), P = 0.01) but no association with overweight. These results were consistent with the pooled results from our meta-analysis study (for diabetes, rs8050136, P = 1.3 x 10(-3); rs9939609, P = 9.8 x 10(-4); for obesity, rs8050136, P = 2.2 x 10(-7); rs9939609, P = 9.0 x 10(-9)). Our findings indicate that the two variants (rs9939609 and rs8050136) in the FTO gene contribute to obesity and T2D in the Asian populations.
Obesity (Silver Spring) 2010 Aug
PMID:Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. 2127 10

Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes.
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PMID:Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. 2008 Jul 51

The effects of FTO on body weight, body composition, and the risk of developing overweight and obesity in children, adolescents, and adults are analyzed in this review. Most trails have been conducted on the rs9939609 SNP of the FTO gene. The minor A-allele frequency ranged from 0.38 to 0.49 in different European populations. Briefly, it has been reported that overweight-obesity risk per A-allele ranged from 1.76 to 1.35, whereas z-score for BMI has a wider variation from 0.05 to 0.5 kg/m(2) in European children and adolescents. As for other adiposity indexes, a waist circumference increase from 0.60 to 0.95 cm per A-allele was found together with an increase in fat mass from 0.68 to 1.78 kg in European children and adoles-cents. In regard to food intake, AA carrier subjects were reported to have reduced satiety responsiveness scores and a higher total energy and fat intake. However, it is not clear whether energy expenditure did modify the role of the rs9939609 FTO gene variant in adiposity. Furthermore, few reports examined the influence of FTO gene variants using intervention studies. Overall, it seems that the A-allele (rs9939609 FTO) is associated with higher body weight gain. However, further studies into FTO gene variants in children and adults are needed.
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PMID:Effects of the FTO gene on lifestyle intervention studies in children. 2009 Mar 91

Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2.5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2.5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.
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PMID:Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats. 2009 39


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