Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We explored peroxisome proliferator-activated receptor-gamma co-activator 1alpha gene (PPARGC1A), peroxisome proliferator-activated receptor-gamma gene (PPARG), and transcription factor A mitochondrial gene (Tfam) promoter DNA methylation in newborns between both extremes of abnormal fetal growth: Small (SGA) and large for gestational age (LGA) in relation to the mother's characteristics. We further sought for the association of rs9930506 variant at FTO gene and the promoter patterns of DNA methylation in the aforementioned genes, in relation to the offspring's birth weight. In a cross-sectional study, 88 healthy pregnant women and their babies were included. According to the offspring birth weight, there were 57 newborns with appropriate weight for gestational age (AGA), 17 SGA, and 14 LGA. After bisulphite treatment of umbilical cord genomic DNA, a real-time methylation-specific PCR was used to determine the promoter methylation status in selected CpGs. Promoter methylated DNA/unmethylated DNA ratio, expressed as mean +/- s.e., was 0.82 +/- 0.15 (45% of alleles) for PPARGC1A, and 0.0044 +/- 0.0006 (0.4% of alleles) for Tfam. PPARG promoter was almost 100% methylated in all samples. In univariate analysis, there was no association among characteristics of the newborn and gene promoter methylation. None of the maternal features were related with the status of promoter methylation, except for a positive correlation between maternal BMI and PPARGC1A promoter methylation in umbilical cord (Pearson correlation coefficient r = 0.41, P = 0.0007). Finally, FTO rs9930506 AA homozygous in the LGA group showed decreased levels of methylated PPARGC1A in comparison with AG + GG genotypes and AGA and SGA infants. In conclusion, our findings suggest a potential role of promoter PPARGC1A methylation in metabolic programming.
Obesity (Silver Spring) 2009 May
PMID:Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns. 1914 28

We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).
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PMID:Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. 1917 33

Both rs17782313 (near MC4R) and rs1421085 (FTO) polymorphisms have been consistently associated with increased risk of obesity and with body mass index (BMI) variation. An effect of both polymorphisms on satiety has recently been suggested. We genotyped rs17782313 and rs1421085 in 5764 relatives from 1109 French pedigrees with familial obesity, 1274 Swiss class III obese adults as well as in 4877 French adults and 5612 Finnish teenagers from two randomly selected population cohorts. In all subjects, eating behaviour traits were documented through questionnaires. We first assessed the association of both single nucleotide polymorphisms with BMI and then studied eating behaviour. Under an additive model, the rs17782313-C MC4R allele showed a trend towards higher percentages of snacking in both French obese children (P=0.01) and Swiss obese adults (P=0.04) as well as in adolescents from the Finnish general population (P=0.04). In French adults with familial obesity, this allele tended to be also associated with a higher Stunkard hunger score (P=0.02) and in obese children with a higher prevalence of eating large amounts of food (P=0.04). However, no consistent association of the FTO rs1421085-C allele and available eating behaviour trait was found in our studied populations. The rs17782313-C allele nearby MC4R may modulate eating behaviour-related phenotypes in European obese and randomly selected populations, in both children and adults, supporting a regulatory role of this genetic variant on eating behaviour, as previously shown for MC4R non-synonymous loss-of-function mutations. The potential effect of the obesity-associated FTO gene on eating behaviour deserves additional investigation.
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PMID:Common genetic variation near MC4R is associated with eating behaviour patterns in European populations. 1915 81

Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P < 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6 kg) and had more total (+2.4 kg), gynoid (+191 g) and abdominal (+136 g) adipose tissue than those in the lowest quintile (all P < 0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n = 193/594 cases/controls) being at 1.55-fold (95% CI 1.21-1.99; P < 0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n = 130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.
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PMID:Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden. 1916 86

The common single-nucleotide polymorphism in the FTO (fat mass and obesity associated) gene is consistently associated with an increased risk of obesity. However, the knowledge of a potential modifying effect of the FTO gene on changes in body weight achieved by lifestyle intervention is limited. We examined whether the FTO gene variant (rs9939609, T/A) is associated with body weight and BMI and long-term weight changes in the Finnish Diabetes Prevention Study (DPS). Altogether, 522 (aged 40-65 years; BMI >or=25 kg/m(2)) subjects with impaired glucose tolerance (IGT) were randomized to control and lifestyle intervention groups. SNP rs9939609 was genotyped from 502 subjects. At baseline, those with the AA genotype had higher BMI than subjects with other genotypes (P = 0.006). The association was observed in women (P = 0.016) but not in men. During the 4-year follow-up, the subjects with the AA genotype had consistently the highest BMI (P = 0.009) in the entire study population. The magnitude of weight reduction was greater in the intervention group, but the risk allele did not modify weight change in either of the groups. Our results confirm the association between the common FTO variant and BMI in a cross-sectional setting and during the long-term lifestyle intervention. We did not observe association between FTO variant and the magnitude of weight reduction achieved by long-term lifestyle intervention. Based on the results from the DPS, it is unlikely that the common variant of the FTO gene affects the success of lifestyle modification on weight loss.
Obesity (Silver Spring) 2009 Apr
PMID:The common variant in the FTO gene did not modify the effect of lifestyle changes on body weight: the Finnish Diabetes Prevention Study. 1918 72

Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.
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PMID:Inactivation of the Fto gene protects from obesity. 2036 Jun 86

Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (approximately 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
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PMID:Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. 1925 36

Multiple studies have identified FTO gene variants associated with measures of adiposity in European-derived populations. The objective of the study was to determine whether FTO variants were associated with adiposity, including visceral and subcutaneous adipose tissue (VAT, SAT), and glucose homeostasis measures in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A total of 27 SNPs in FTO intron 1, including SNPs prominent in the literature (rs9939609, rs8050136, rs1121980, rs17817449, rs1421085, and rs3751812), were genotyped in 1,424 Hispanic Americans and 604 African Americans. Multiple SNPs were associated with BMI and SAT (P values ranging from 0.001 to 0.033), and trending or associated with waist circumference (P values ranging from 0.008 to 0.099) in the Hispanic Americans. No association was observed with VAT, illustrating that FTO variants are associated with overall fat mass instead of specific fat depots. For the glucose homeostasis measures, variants were associated with fasting insulin but, consistent with other studies, after BMI adjustment, no evidence of association remained. The lack of association of FTO SNPs with insulin sensitivity is consistent with the lack of association with VAT, since these traits are strongly correlated. In the African Americans, only rs8050136 and rs9939609 were associated with BMI and WAIST (P values of 0.011 and 0.034), and associated or trending towards association with SAT (P values of 0.038 and 0.058). These results confirm that FTO variants are associated with adiposity measures, predisposing individuals to obesity by increasing overall fat mass in Hispanic Americans and to a lesser degree in African Americans.
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PMID:Analysis of FTO gene variants with measures of obesity and glucose homeostasis in the IRAS Family Study. 1932 89

Here we explore whether there is any evidence that the rapid development of the obesity epidemic in emerging nations, and its unusual coexistence with malnutrition, may have evolutionary origins that make such populations especially vulnerable to the obesogenic conditions accompanying the nutrition transition. It is concluded that any selection of so-called 'thrifty genes' is likely to have affected most races due to the frequency and ubiquity of famines and seasonal food shortages in ancient populations. Although it remains a useful stimulus for research, the thrifty gene hypothesis remains a theoretical construct that so far lacks any concrete examples. There is currently little evidence that the ancestral genomes of native Asian or African populations carry particular risk alleles for obesity. Interestingly, however, there is evidence that a variant allele of the FTO gene that favors leanness may be less active in Asians or Africans. There is also some evidence that Caucasians may be less prone to developing type 2 diabetes mellitus than other races suggesting that there has been recent selection of protective alleles. In the near future, recently developed statistical methods for comparing genome-wide data across populations are likely to reveal or refute the presence of any thrifty genes and might indicate mechanisms of vulnerability.
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PMID:Obesity in emerging nations: evolutionary origins and the impact of a rapid nutrition transition. 1934 67

The association of the FTO gene with obesity has been implicated in various human populations. The FTO gene is also most likely involved in the regulation of energy balance and feed intake. Here, the FTO gene was studied as a candidate gene for fatness and growth rate traits in pigs. The amino acid sequence of the FTO gene showed high conservation among human, pig, and other important domestic animals. Twelve variants including ten SNPs and two indels were detected, and then five SNPs within different genomic regions were genotyped in the ISU Berkshire x Yorkshire pig resource family. The linkage disequilibrium analyses revealed that most of these FTO variants were not in strong LD with each other. The SNPs c.46-139A > T within intron 1 and a synonymous mutation c.594C > G (Ala198Ala) within exon 3 had significant (P < 0.01) associations with average daily gain on test and total lipid percentage in muscle, respectively. Five major haplotypes were identified and the subsequent association analyses suggested that haplotype 2 (-CTTGG-) was the most favorable for increased growth rate, while haplotype 1 (-CTACG-) was unfavorably associated with intramuscular fatness traits.
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PMID:The fat mass and obesity-associated (FTO) gene is associated with intramuscular fat content and growth rate in the pig. 1937 Apr 55


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